REVIEW ARTICLE OPEN
Cellula and Molecula Biology
Me abolic adap a ions in p os a e cance
Mikel Pujana-Vaque izo
1,2
, Lau a Bozal-Bas e a
1
✉and A kai z Ca acedo
1,2,3,4,5
✉
© The Au ho (s) 2024
P os a e cance is one o he mos commonly diagnosed cance s in men and is a majo cause o cance - ela ed dea hs wo ldwide.
Among he molecula p ocesses ha con ibu e o his disease, he weigh o me abolism has been placed unde he limeligh in
ecen yea s. Tumou s exhibi me abolic adap a ions o comply wi h hei biosyn he ic needs. Howe e , me aboli es also play an
impo an ole in suppo ing cell su i al in challenging en i onmen s o emodelling he umou mic oen i onmen , hus being
ecognized as a hallma k in cance . P os a e cance is uniquely d i en by and ogen ecep o signalling, and his knowledge has also
influenced he pa hs o cance me abolism esea ch. This e iew p o ides a comp ehensi e pe spec i e on he me abolic
adap a ions ha suppo p os a e cance p og ession beyond and ogen signalling, wi h a pa icula ocus on umou cell in insic
and ex insic pa hways.
B i ish Jou nal o Cance (2024) 131:1250–1262; h ps://doi.o g/10.1038/s41416-024-02762-z
INTRODUCTION
The and ogen ecep o (AR) is a cen al playe in he biology o
he p os a e, ope a ing as a nuclea ecep o essen ial o no mal
p os a e de elopmen and unc ion [1]. AR media es he e ec s o
and ogens and egula es he exp ession o genes in ol ed in
p os a e g ow h, main enance, and di e en ia ion. Beyond
de elopmen al s ages, AR also influences p os a e heal h
h oughou adul hood [2]. AR signalling is linked o he onse
and p og ession o p os a e cance (PCa), whe e i becomes a
p ima y d i e o umou g ow h. The e o e, inhibi ion o AR
unc ion ep esen s he a ge ed he apy in his disease [3]. AR
ep og ams PCa cellula me abolism, c ea ing a unique molecula
scena io ha has been documen ed o he las 100 yea s [4].
Ne e heless, he complexi y unde lying cellula me abolism
ex ends beyond AR signalling, which is en isioned o o e
inno a i e he apeu ic oppo uni ies. Ou cu en unde s anding
o cellula me abolism encompasses aspec s such as he umou
mic oen i onmen (TME) o die . In his e iew, we will explo e
majo me abolic pa hways suppo ing PCa p og ession and
me as asis, wi h special emphasis on umou cell-in insic and
ex insic glucose, lipid and one-ca bon me abolism (1 C me abo-
lism), while o he ele an p ocesses including he connec ion
be ween me abolism and epigene ics will be le ou o he scope
o his wo k. Fu he mo e, we will inco po a e new e idence om
o he umou ypes o iden i y sha ed cha ac e is ics ha can
apply o PCa.
MAJOR METABOLIC ALTERATIONS IN PROSTATE
CANCER CELLS
Glucose me abolism
Glycolysis and he Wa bu g e ec . Glycolysis me abolises glucose
o py u a e ia a se ies o in e media e eac ions, gene a ing ATP
and NADH (Fig. 1). Cance cells o en exhibi inc eased glycoly ic
ac i i y o gene a e lac a e, e en in he p esence o oxygen,
known as ae obic glycolysis o he Wa bu g e ec [5]. Despi e i s
lowe e ficiency compa ed o oxida i e phospho yla ion (OXPHOS)
in he mi ochond ia, cance cells hea ily depend on his pa hway
o p oduce ene gy. I is impo an o s a e ha he inc ease o
anae obic glucose u ilisa ion does no imply a educ ion in
mi ochond ial OXPHOS ac i i y, in con as o he ini ial hypo h-
esis o D . O o Wa bu g [6]. Al hough se e al hypo heses ha e
been p oposed, he eason why p oli e a ing cells me abolise
glucose p edominan ly o p oduce lac a e emains elusi e. Two
complemen a y publica ions a gue ha when he demand o
NAD+exceeds he demand o ATP, esul ing in he sa u a ion o
he mi ochond ial NADH, umou cells en o ce ae obic glycolysis
e en in he p esence o oxygen [7,8]. These me abolic
adap a ions ha e been b ough om bench o bedside h ough
di e en app oaches. On he one hand, ae obic glycolysis esul s
in an ele a ed demand o glucose, which has inspi ed he
de elopmen o cance -moni o ing s a egies based on he up ake
o
18
F-fluo odeoxyglucose wi h posi on emission omog aphy
(PET) [9]. On he o he hand, al hough al e a ions in copy numbe
Recei ed: 13 Ma ch 2024 Re ised: 7 June 2024 Accep ed: 11 June 2024
Published online: 5 July 2024
1
Cen e o Coope a i e Resea ch in Biosciences (CIC bioGUNE), Basque Resea ch and Technology Alliance (BRTA), Bizkaia Technology Pa k, Building 801A, 48160 De io, Spain.
2
Cen o de In es igación Biomédica En Red de Cánce (CIBERONC), 28029 Mad id, Spain.
3
T asla ional P os a e Cance Resea ch Lab, CIC bioGUNE-Basu o, Biobizkaia Heal h
Resea ch Ins i u e, Ba acaldo, Spain.
4
Ike basque, Basque Founda ion o Science, Bilbao, Spain.
5
Biochemis y and Molecula Biology Depa men , Uni e si y o he Basque
Coun y (UPV/EHU), Leioa, Spain. ✉email: [email p o ec ed]; aca[email p o ec ed]
www.na u e.com/bjc B i ish Jou nal o Cance
1234567890();,:
ha e been epo ed in glycolysis-p omo ing genes [10], de egu-
la ed mRNA exp ession ep esen s a key con ibu ing ac o o
ae obic glycolysis, which suppo ed he de elopmen o an-
sc ip omic gene signa u es in di e en cance ypes [11–13].
And ogen ecep o plays a p edominan ole in con olling he
exp ession o g ow h-p omo ing and an i-apop o ic genes
in ol ed in a ious me abolic p ocesses, such as glycolysis [14].
Glucose anspo e s GLUT1 and GLUT2 a e egula ed a he
ansc ip ional le el by he AR [15–17], whe eas con ol by AR-
independen ac o s such as SOX2 and MYC p omo es p os a e
cance p og ession, lineage plas ici y, and he apy esis ance
[18,19]. In e es ingly, he Wa bu g e ec is obse ed bo h in
localised PCa [20,21], as well as in ad anced disease o me as a ic
lesions [22–24]. In his line, i has been epo ed ha he highes
lac a e le els a e ound in pa ien s wi h PTEN loss, a gene ic
ea u e o ad anced PCa [25]. The ac i a ion o he
PI3K–AKT–mTOR signalling pa hway is belie ed o be a key ac o
in PTEN-deficiency-d i en p os a e umo igenesis p omo ing
ae obic glycolysis [26,27]. Inhibi ion o MCT4 (a plasma
memb ane lac ic acid anspo e ), has been pos ula ed as a
he apeu ic s a egy o educe glycolysis and lac ic acid sec e ion
in neu oendoc ine p os a e cance (NEPC), a sub ype o agg essi e
PCa [28]. In NEPC cell lines, inhibi ing MCT4 exp ession educed
cell p oli e a ion in i o and glucose me abolism by down-
egula ing glycoly ic genes. Howe e , da a abou he e ec i eness
and oxici y o MCT4 inhibi ion in NEPC models in i o a e s ill
lacking.
Despi e he ele ance o glycolysis o umou cells, accumula -
ing e idence sus ains ha bo h he ica boxylic acid (TCA) cycle
and he OXPHOS pa hway a e s ill p esen and ac i e in he
me as a ic se ing [6,29–36], which could complica e he use o
lac a e- a ge ed he apies [27]. A p omising new small molecule,
BKIDC-1553 (which exhibi s good sa e y and pha macologic
p ope ies), has been shown o selec i ely inhibi he g ow h o
PCa cell lines h ough i s an i-glycoly ic ac i i y. This is achie ed by
inhibi ing hexokinase 2, as epo ed in a p eclinical xenog a
model o ad anced PCa. The selec i e g ow h inhibi ion ac i i y o
BKIDC-1553 is equi alen o ha o enzalu amide [37]. All hese
esul s demons a e he complexi y and impac o me abolic
in e ac ions wi hin umou s and in di e en s ages, highligh ing
he impo ance o s udying d ug e ec s in di e se me abolic
scena ios.
T ica boxylic acid cycle (TCA) and oxida i e phospho yla ion
(OXPHOS). The TCA comp ises a se ies o mi ochond ial chemical
eac ions and is esponsible o p oducing ene gy and me abolic
in e media es. I begins wi h he con e sion o ace yl-CoA (which
is p oduced om he b eakdown o ca bohyd a es, a s, and
p o eins) and oxaloace a e in o ci a e. Th ough a se ies o
enzyma ic eac ions, ci a e is ans o med, esul ing in he
p oduc ion o ca bon dioxide and molecules ca ying high-
ene gy elec ons, namely NADH and FADH2. These elec on
ca ie s a e subsequen ly u ilised o OXPHOS, a p ocess ha
occu s in he inne mi ochond ial memb ane. OXPHOS in ol es
he elec on anspo chain (ETC) and a p o on g adien ,
ul ima ely leading o he p oduc ion o ATP (Fig. 1). Despi e he
ini ial pe cep ion o a gene al educ ion o he use o glucose
de i a i es in he mi ochond ia, ecen e idence shows ha he e
is umou - ype specifici y in his ep og amming. Whe eas
panc eas, lung and colon umou s exhibi a slowe ATP p oduc ion
han heal hy issues, b eas cance -de i ed me as ases epo edly
show as e TCA cycle a e han o ho opic p ima y umou s [38].
In line wi h hese esul s, an inc ease in OXPHOS gene exp ession
was de ec ed in melanoma b ain me as asis (MBM) by di ec
me aboli e p ofiling and [U-
13
C]-glucose acing in i o [39], which
is associa ed o inc eased sensi i i y o hese lesions o
pha macological OXPHOS inhibi ion [39]. Howe e , la e clinical
ials o analyse he he apeu ical po en ial o he same OXPHOS
inhibi o in ad anced solid umou s and acu e myeloid leukaemia
showed only modes a ge inhibi ion and limi ed an i umou
ac i i y a ole a ed doses and led o discon inua ion o he ials
due o neu o oxici y [40]. In e es ingly, umou cells exhibi
changes in he TCA ha go beyond he egula ion o i s ac i i y.
Mu a ions in he TCA cycle o he ETC machine y induce
TCA
cycle
Glucose
Heal hy p os a e luminal cell
Ci a e
Glucose
Cy oplasm
Py u a e
Zinc
Zinc Aconi ase Ci a e
STOP
ATP
NADH
Mi ochond ia
Ci a e
Lac a e Lac a e
ATP
TCA
cycle
Glucose
P os a e cance
Ci a e
Glucose
Cy oplasm
Py u a e
Zinc Aconi ase
NADH
Mi ochond ia
Me as asis
Lac a e
Glucose
Ci a e
Glucose
Cy oplasm
Py u a e
Aconi ase
NADH
Mi ochond ia
Glucose 6P
F uc ose 6P
PPP
G
lycolysi
s
O
XPH
OS
HBP
G6PD
Glycosida ion
ATP
Glucose 6P
F uc ose 6P
Glycosyla ion
ATP
6GPD
NADPH
G6PD 6GPD
G
l
y
col
y
si
s
Gl
y
col
y
si
s
ATP
Glucose 6P
F uc ose 6P
HBP
H
BP
O
XPH
OS
O
XPH
OS
PPP
PPP
Glycosyla ion ?
NADPH
G6PD 6GPD
abc
TCA
cycle
ATP
Lipids
Lipogenesis
Lipids
Lipogenesis
Zinc
NADPH
Fig. 1 Schema ic o e iew o he me abolic ewi ing occu ing in p os a e epi helial cells du ing he di e en s ages o cance
p og ession. a Heal hy p os a e luminal cells accumula e high le els o zinc (due o he o e exp ession o i s anspo e ), leading o he
inhibi ion o mi ochond ial aconi ase, he key enzyme esponsible o he ci a e-isoci a e con e sion in he TCA cycle. This inhibi ion esul s
in he unca ion o he TCA cycle and ci a e accumula ion and sec e ion. As a esul , no mal p os a e epi helial cells a e cha ac e ized by an
ine ficien OXPHOS. bIn p os a e cance cells, in acellula zinc le els a e significan ly educed (due o a dec eased exp ession o i s
anspo e ); his leads o he eac i a ion o aconi ase, es o ing he ci a e-isoci a e con e sion, and consequen ly o he TCA cycle and
OXPHOS me abolic pa hways. In addi ion, bo h he hexosamine biosyn hesis pa hway (HBP) esul ing in glycosyla ion and he pen ose
phospha e pa hway (PPP) ha gene a es NADPH and nucleo ides a e up egula ed in PCa cells. cMe as a ic PCa cells exhibi he Wa bu g
e ec wi h pe sis en TCA cycle/OXPHOS and PPP ac i i y. C ea ed wi h BioRende .com.
M. Pujana-Vaque izo e al.
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B i ish Jou nal o Cance (2024) 131:1250 – 1262
al e na i e me abolic ou es, such as educ i e ca boxyla ion
obse ed in a ious cance ypes [41–47]. Beyond he e ec o
mu a ions al e ing he TCA cycle, specific cell s a e ansi ions
a e accompanied by p o ound TCA ep og amming comp ising
he ex ami ochond ial use o ci a e ha egene a es oxaloace-
a e [48].
P os a e epi helial cells do no oxidise he p oduced ci a e like
mos no mal cells due o unca ed TCA cycle [49–53]. Ins ead,
luminal p os a e cells, bu no basal cells [54], accumula e high
mi ochond ial zinc (Zn
2+
). Zn
2+
inhibi s he mi ochond ial enzyme
(m)-aconi ase, esponsible o ci a e oxida ion, and he accumu-
la ed ci a e is subsequen ly sec e ed in o he p os a ic fluid. While
basal cells p e e en ially gene a e ci a e h ough py u a e
dehyd ogenase, luminal cells p edominan ly gene a e ci a e
h ough py u a e ca boxylase ac i i y [54]. Me abolism o
py u a e, aspa a e, glu amine and b anched-chain amino acids
(BCAA) migh con ibu e o eplenishing me aboli es o he
unca ed TCA cycle in PCa [55,56]. AR induces a me abolic
ep og amming encompassing hZIP1 zinc anspo e down-
egula ion ha leads o low mi ochond ial zinc le els [57,58]
and m‐aconi ase eac i a ion, es o ing he TCA cycle [59], and
inc easing he suscep ibili y o PCa cells o OXPHOS inhibi o s [60].
Oxida i e phospho yla ion can be a ge ed by es ic ing he
supply o NADH o by di ec ly inhibi ing componen s o he ETC.
Mu a ions in he mi ochond ial DNA encoding o OXPHOS
machine y p omo e Wa bu g-like me abolism and an an i-
umou immune esponse [61]. Ta ge ing he TCA cycle by
comp omising mi ochond ial subs a e a ficking migh also be
an e ec i e s a egy. Fo example, me o min and o enone,
inhibi o s o complex-I (CI) o he ETC, inhibi p oli e a ion in
se e al human cance cell lines, including PCa [62–64]. E idence
has shown ha me o min has mul iple an ineoplas ic e ec s
h ough AMPK-dependen and independen mechanisms, namely
he al e a ion o IGF-1 signalling pa hways, supp ession o AR o
mTOR pa hway, and lipogenesis. In line wi h his no ion, he e is
e idence o educed mo ali y in PCa pa ien s ea ed wi h
me o min [64]. The o enone de i a i e deguelin exhibi s
an i umou al ac i i y in p eclinical mouse models o PCa based
on he combined loss o P en and T p53 [65]. This e ec is
associa ed o he al e na i e use o he ETC by P en-deficien cells,
which consume ATP h ough mi ochond ial complex V ins ead o
p oducing i . This obse a ion could be ansla ed o he use o CI
inhibi o s in PCa pa ien s s a ified by PTEN s a us. Whe eas mos
PCa esea ch is ocused on he e ec o AR signalling p omo ing
TCA cycle [66,67], a deepe unde s anding o he AR-independen
me abolic al e a ions is lacking and could be c i ical when
designing he apeu ic s a egies in cas a ion- esis an pa ien s.
Amino acid me abolism o he pen ose phospha e
pa hway (PPP). The PPP is a main p oduce o NADPH and
nucleic acid p ecu so s [68], which helps umou cells balance he
edox s a us. Tumou cells exhibi de egula ion o oncogenes and
umou supp esso genes ha con ol his pa hway [69]. Gene ic
deficiency in glucose-6-phospha e dehyd ogenase (G6PD), one o
he a e-limi ing enzymes o he PPP, is a common inhe i ed
enzyme de ec and occu s almos exclusi ely in males [70–72].
The e is inc easing e idence ha his deficiency may o e
p o ec ion agains s omach, colon, and li e cance . Con e sely,
G6PD up egula ion has been associa ed wi h highe cance isk
[73]. In as p oli e a ing cells, a high NADP
+
/NADPH a io ac i a es
G6PD o suppo NADPH p oduc ion, leading o educ i e
biosyn hesis o a y acids and nucleo ides. Fu he mo e, NADPH
p omo es cell su i al unde oxida i e s ess condi ions such as
mi ochond ial dys unc ion [74]. Up egula ed G6PD ac i i y is
obse ed in a ious cance s, including papilla y hy oid ca cinoma,
colo ec al, enal, hepa ocellula , b eas , and PCa [75–81]. Mechan-
is ic esea ch in PCa cell lines sugges s ha AR-media ed
egula ion o he PPP occu s h ough up egula ion o G6PD in
esponse o mTOR complex 1 ac i a ion, leading o he p oduc ion
o nucleo ide p ecu so s o DNA syn hesis and NADPH o
p omo e lipogenesis [82] (Fig. 1). Indeed, PPP and G6PD ha e
been p oposed as me abolic a ge s o PCa bone me as asis
ea men [83]. In i o, gene ic and pha macological G6PD
inhibi ion dec eased cance g ow h and mig a ion, leading o
al e a ions in cellula edox balance and heigh ened sensi i i y o
chemo he apy. In i o, G6PD gene ic abla ion esul ed in he
educ ion o bone me as a ic bu den. A ecen s udy e ealed ha
ano he PPP- ela ed enzyme, 6PGD, plays a key ole in PCa g ow h
and su i al by coun e ac ing oxida i e s ess and unco e ed a
no el eedback mechanism linking 6PGD and he AR signalling
axis ha opens a new he apeu ical window o co- a ge ing AR
and he PPP [84]. Gene ic o pha macological inhibi ion o 6PGD
using physcion and S3 showed an icance ac i i y in agg essi e,
cas a ion- esis an disease models as well as pa ien -de i ed
umou explan s, pa ly due o inc eased oxida i e s ess.
Ta ge ing o 6PGD was associa ed wi h wo impo an umou -
supp essi e mechanisms: fi s ly, i inc eased he ac i i y o he
AMP-ac i a ed p o ein kinase (AMPK); secondly, i enhanced AR
ubiqui yla ion, leading o a educ ion in AR p o ein le els and
ac i i y. Pha macological co- a ge ing o bo h ac o s was mo e
e ec i e in supp essing he g ow h o PCa cells han single-agen
he apies, indica ing posi i e eedback be ween AR and 6PGD. All
hese findings sugges ha he PPP could be a aluable sou ce o
a ge s o an icance d ug design and he apeu ic combina ion.
Hexosamine biosyn he ic pa hway (HBP). The HBP is a me abolic
ou e ha edi ec s 2–5% o glucose-de i ed ca bons away om
glycolysis in non-cance cells. I comp ises he con e sion o he
glycoly ic in e media e uc ose-6-phospha e o p oduce UDP-N-
ace ylglucosamine (UDP-GlcNAc) [85]. UDP-GlcNAc se es as a
subs a e o a ious cellula p ocesses, including p o ein glyco-
syla ion—a c ucial pos - ansla ional modifica ion whe e suga s
a e a ached o p o eins and lipids. Cance cells up egula e he
flux owa ds he HBP and UDP-GlcNAc syn hesis by inc easing
glucose and glu amine in ake o in esponse o oncogenic-
associa ed signals like Ras [86], mammalian a ge o apamycin
complex 2 (mTORC2) [87,88], and ans o ming g ow h ac o be a
(TGF-β)[89]. In line wi h inc eased UDP-GlcNAc le els, b eas
[90,91], lung [92], colon [92], li e [93], endome ial [94], ce ical
[95], panc ea ic cance [96] and PCa [97] cells exhibi inc eased
O-GlcNAcyla ion (Fig. 1). The e a e di e se molecula al e a ions
ha con e ge on inc eased syn hesis o glycans. The second- a e
limi ing enzyme o he HBP, UAP1 [98–100], is ele a ed in PCa,
which p o ec s umou cells om ER s ess-induced cell dea h,
hus pos ula ing i as a iable a ge o cance he apy. An
enzyme in ol ed in he conjuga ions p ocess, he glycosyl ans-
e ase GALNT7, is also up egula ed in PCa issues and p omo es
p os a e umou g ow h [101]. Lessons om o he umou ypes
e eal he me abolic c oss alk ha balances he use o glucose
in e media y me aboli es. Loss o he PHGDH, an enzyme in ol ed
in glucose-de i ed se ine biosyn hesis p omo es me as asis by
ewi ing glucose owa ds HBP, hus inc easing in eg in glycosyla-
ion [102].
Inc eased glycosyla ion influences he s uc u al di e si y in
p o eins, including sialyla ion, ucosyla ion, O-β-N-ace ylglucosyla-
ion, and he p esence o c yp ic and high-mannose N-glycans and
p o eoglycan al e a ions [103]. Based on he e idence p esen ed,
he apeu ic a ge ing o HBP ises as an inno a i e s a egy o
selec i ely a ec cance cells, as non- ans o med cells would be
mo e esilien o he pe u ba ion in O-GlcNAcyla ion [104,105].
Hexosamine analogues could se e his pu pose since hey exhibi
an i umo al p ope ies. O he p omising he apeu ic s a egies in
p eclinical models in ol e he pha macological inhibi ion o OGT,
he HBP enzyme ha ca alyses he addi ion o he GlcNAc esidue
o a ge p o eins. On he one hand, inhibi ing O-GlcNAcyla ion in
PCa cells educed he exp ession o ma ix me allop o einase
M. Pujana-Vaque izo e al.
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B i ish Jou nal o Cance (2024) 131:1250 – 1262
MMP-2, MMP-9, and VEGF, esul ing in inhibi ion o in asion and
angiogenesis media ed by he egula ion o he oncogenic
ansc ip ion ac o FoxM1 [104]. On he o he hand, OGT
inhibi ion educed he p oli e a ion o PCa cells due o sus ained
loss o c-MYC [97]. As a no e o cau ion, he equi emen o HBP
o PCa cells migh be umo s age-dependen . In ac , cas a ion-
esis an PCa shows dec eased HBP me aboli e and enzyme le els,
sugges ing ha a ge ing he pa hway in his pa hological se ing
could ha e unp edic able biological consequences [106]. O e all,
unde s anding he unc ion and composi ion o glycop o eins and
glycans ac oss all s ages o PCa will likely be c ucial o imp o ing
disease managemen . The ele ance o he cell su ace glycan
p ofile o cell-cell in e ac ions an icipa es ha HBP and glycosyla-
ion ewi ing will ha e p o ound implica ions in he in e ac ions o
umou cells wi h he TME.
Lipid me abolism
Lipid me abolic ep og amming encompasses al e a ions in
a ious aspec s o lipid me abolism, including syn hesis, s o age,
and ca abolism [107]. One significan adap a ion is he up egula-
ion o lipogenic pa hways, whe e cance cells enhance he
p oduc ion o a y acids and o he lipid componen s o sus ain
hei apid g ow h. This inc ease in lipogenesis o en in ol es he
ac i a ion o key enzymes such as ATP ci a e lyase (ACLY) and
ace yl-CoA ca boxylase (ACC), d i en by oncogenic signalling
pa hways like he PI3K/Ak /mTOR axis and MYC [108]. Addi ionally,
cance cells exhibi changes in lipid up ake and u iliza ion, elying
on bo h endogenous and exogenous lipid sou ces o sus ain hei
me abolic needs.
Dys egula ion o lipid me abolism is conside ed a hallma k in
PCa [109]. These umou cells display dis inc al e a ions in lipid
me abolism compa ed o no mal p os a e coun e pa s, and hese
changes a e associa ed wi h umou g ow h, su i al, and
me as asis [109]. Whe eas al e a ions in oncogenes and umou
supp esso genes (p53 loss, PTEN loss, PI3K mu a ions) ha a e
sha ed ac oss di e en umou ypes can al e his p ocess,
enhanced lipid me abolism in PCa is p edominan ly d i en by AR
signalling [110,111]. Indeed, AR con ols he ansc ip ion o
enzymes in ol ed in a y acid syn hesis and oxida ion o ulfil he
bioene ge ic and anabolic demands o PCa cells, and i also
egula es lipid up ake and s o age, choles e ol, and phospholipid
me abolisms [112] (Fig. 2).
De no o lipogenesis (DNL). PCa is cha ac e ised by augmen ed
DNL in bo h in ea ly and la e s ages o he disease [113]. This
pa hway is igh ly egula ed and p oduces a y acids om non-
lipidic p ecu so s. The p ima y subs a e in a y acid syn hesis is
ace yl-CoA, which is ca boxyla ed by ace yl-CoA ca boxylase o
o m malonyl-CoA [114]. Malonyl-CoA uni s a e hen sequen ially
added o he g owing a y acid chain by a y acid syn hase
Kidney
Bladde
P os a e
AR
SREBP
Ci a e
Ace yl - CoA
Malonyl - CoA
Palmi a e
SFA MUFA
Ace oace yl - CoA
HMG - CoA
Me alona e
Choles e ol
SREBP a ge genes
de no o lipogenesis Choles e ol
biosyn hesis
ACAT
ACAC
ACLY
FASN
Lipid d ople s s o age
Exogenous lipid up ake
LDL
LDLRFATPs CD36
ELOVL
SCD
FADS
ELOVL
HMGCS
HMGCR
Acyl-CoA
CPT1
FABP5
Fa y acid
Fa os a in
C75
Du as e ide
Fa y acid
oxida ion
Co egula o s
AR a ge genes
AR AR
AR AR
AR
AR
Hsp
Hsp
5α- educ ase
DHT
Tes os e one
AR media ed lipid
me abolism in PCa
Tumo al cell
Al e ed lipid me abolism in
he TME?
S a ins
Neu ophil
Mac ophage
Dend i ic cell
T-Cell
Endo helial cell
Fa y acid
Fa y acid
Fa y acid
Nucleus
Mi ochond ia
Cy oplasm
SBFI-103
ATGL
MAGL
Lipolysis
SQLE
FR194738
Te bina ine
Fig. 2 The landscape o lipid me abolism in PCa. The figu e illus a es he key aspec s o lipid me abolism in PCa, mainly d i en by
AR-media ed cellula ep og amming o umo al cells. In esponse o AR signalling, PCa cells exhibi an augmen ed de no o lipogenesis
h ough ansc ip ional egula ion by SREBPs. Mi ochond ial a y acid oxida ion, ia up egula ion o he CPT1 anspo e , gene a es ene gy
o p oli e a ion. In addi ion, PCa cells inc ease exogenous a y acid up ake h ough up egula ed CD36 and FATPs. FABPs play a ole in he
in acellula compa men aliza ion o a y acids. Dys egula ion o choles e ol me abolism also ep esen s a cha ac e is ic ea u e o p os a e
umou s. The main enzymes and egula o s aking pa in hese pa hways a e highligh ed, alongside a ious inhibi o s s udied o po en ial
he apeu ic in e en ions. Finally, he s udy o lipid me abolism in cells comp ising he TME eme ges as an impo an s a egy o u u e
esea ch. Abb e ia ions: AR; and ogen ecep o , DHT; dihyd o es os e one. C ea ed wi h BioRende .com.
M. Pujana-Vaque izo e al.
1253
B i ish Jou nal o Cance (2024) 131:1250 – 1262
(FASN). This p ocess con inues h ough a se ies o chemical
eac ions un il a long-chain a y acid is syn hesised. The esul ing
a y acids can be u he modified, inco po a ed in o phospho-
lipids o memb ane biogenesis, o s o ed as iglyce ides [115].
S e ol- egula o y elemen -binding p o eins (SREBPs) a e an-
sc ip ion ac o s ha play a c ucial ole in egula ing lipid syn hesis.
SREBP-1 is up egula ed along PCa p og ession [111,112], pa ly in
an AR-dependen manne [116,117], and i ac i a es he exp ession
o enzymes in ol ed in de no o lipogenesis, including FASN
[118,119].
Di e en s a egies ha e been de eloped o a ge DNL in PCa.
P eclinical s udies using SREBP inhibi o s such as a os a in suppo
he idea ha a ge ing his pa hway is an in e es ing s a egy o
block PCa g ow h and p omo e apop osis [120]. Fa os a in inhibi s
SREBP clea age-ac i a ing p o ein (SCAP), a key egula o o lipid
me abolism. SCAP is esponsible o anspo ing he SREBPs om
he endoplasmic e iculum (ER) o he Golgi appa a us, whe e hey
unde go p o eoly ic clea age o ac i a e he ansc ip ion o genes
in ol ed in choles e ol and a y acid syn hesis. By inhibi ing SCAP,
a os a in p e en s he ansloca ion o SREBPs o he Golgi, hus
inhibi ing hei ac i a ion and subsequen ansc ip ional egula ion
o lipid syn hesis [120]. In addi ion, du as e ide and C75 a e wo
FASN inhibi o s ha ha e been de eloped and es ed o hei
e ec i eness in PCa [121–123]. Du as e ide indi ec ly educes FASN
mRNA le els by inhibi ing he enzyme 5α- educ ase, which is
esponsible o con e ing es os e one in o dihyd o es os e one
[121]. C75 inhibi s FASN h ough compe i i e binding, hus
p e en ing he syn hesis o a y acids om ace yl-CoA and
malonyl-CoA [122].
Despi e a ious e o s o a ge lipid syn hesis, a c i ical
challenge pe sis s in elucida ing p ecise bioma ke s and me hodol-
ogies o he iden ifica ion o lipogenic umou s and he s a ifica-
ion o pa ien s likely o exhibi op imal esponses o DNL a ge ing.
Fo ha eason, new a ge s o he DNL pa hway a e cu en ly
being explo ed o he apeu ic pu poses. Recen ly, a la ge-scale
analysis e ealed ha he a y acid elongase ELOVL5 is up egula ed
in PCa and i s deple ion leads o an i umo al esponses [124].
Concomi an ly, he ELOVL5 enzyme also gene a es polyunsa u a ed
a y acids (PUFAs), which ha e been associa ed wi h enzalu amide
esis ance du ing neu oendoc ine di e en ia ion (NED) by ac i a -
ing he AKT-mTOR pa hway [125].
Lipolysis and a y acid oxida ion (FAO). Lipolysis e e s o he
p ocess ha con e s s o ed a s o iglyce ides in o glyce ol and
a y acids. In he con ex o PCa, lipolysis is up egula ed o
gene a e a y acids ha a e subsequen ly used as an ene gy
sou ce and building blocks o cellula componen s [126].
Howe e , lipolysis is a mo e complex p ocess han lipid syn hesis.
I equi es a balance be ween a y acid ca abolism, necessa y o
biomass, and he need o ATP and NADPH p oduc ion. Ele a ed
le els o monoacylglyce ol lipase (MAGL) in AR-independen
p os a e cance con ibu e o malignancy h ough endocannabi-
noid and a y acid pa hways [127]. Complemen a ily, adipose
iglyce ide lipase (ATGL) exp ession co ela es wi h wo se
p ognosis in CRPC pa ien s [128]. Inhibi ion o ATGL impai s PCa
cell g ow h in i o and in i o, inducing a me abolic shi owa ds
glycolysis [128].
A e being eleased om s o age uni s, lipids can be
ca abolised h ough a y acid oxida ion (FAO), a p ocess whe e
cells u ilise FAO as an ene gy sou ce, and ha is al e ed in PCa
[129]. CPT1, he enzyme ha anspo s medium-long a y acids
in o he mi ochond ia o oxida ion, is up egula ed in PCa
[130,131]. In addi ion, FAO could sus ain a cas a ion- esis an
s a e, which has been demons a ed ecen ly h ough he
inhibi ion o 2,4-dienoyl-CoA educ ase (DECR1) [132,133].
Fa y acid up ake and anspo . Fa y acid anspo p o eins
(FATPs) and a y acid binding p o eins (FABPs) a e esponsible o
he up ake o exogenous and in acellula anspo o a y acids,
espec i ely. These p o eins a e up egula ed in PCa, which
heo e ically inc eases a y acid a ailabili y o cellula p ocesses
[134,135]. FABP5 inhibi ion p o ides a syne gis ic e ec in
combina ion wi h chemo he apy [136], and he epo ed depen-
dence o PTEN loss-d i en PCa [137] on his enzyme encou ages
he e alua ion o his he apeu ic s a egy in a s a ified
popula ion. Indeed, SBFI-103, a compe i i e inhibi o o FABP5, is
e ec i e and well- ole a ed bo h in i o and in i o in PCa cells
esis an o ADT o axanes [137]. Finally, CD36, a mul i unc ional
cell su ace ecep o ha impo s a y acids, con ibu es o
a ious aspec s o PCa biology, including umou g ow h,
angiogenesis, and me as asis. The umou supp essi e conse-
quences o Cd36 dele ion in P en loss-induced PCa [138] sugges
ha knowledge and he apeu ic s a egies epo ed o o he
umou ypes could be implemen ed in his disease [139,140].
FA6.152, an an i-CD36 neu alising an ibody, inhibi s all known
unc ions o CD36, including i s in e ac ions wi h h ombospondin,
collagens, and a y acids. Simila ly, ano he CD36 a ge ing
an ibody named JC63.1 selec i ely blocks up ake o a y acid
and oxidised low-densi y lipop o eins. T ea men o o al squa-
mous cell ca cinoma (OSCC) models wi h hese wo an ibodies
impai me as asis [139].
Choles e ol me abolism. PCa cells o en exhibi inc eased de no o
choles e ol biosyn hesis [141–143], and AR signalling con ols he
exp ession o choles e ol biosyn he ic enzymes, such as HMG-CoA
educ ase (HMGCR) [144]. The ele ance o his pa hway in PCa
spans mul iple biological aspec s. Fi s , choles e ol is a c i ical
p ecu so o he syn hesis o s e oid ho mones, including
and ogens, which sus ains he ac i a ion o AR in umou cells
a e cas a ion he apy [145–147]. Second, choles e ol is a c i ical
componen o lipid a s, memb ane mic odomains ha play a ole
in cellula signalling. Al e a ions in choles e ol le els a ec lipid
a dynamics and he associa ed signalling pa hways in ol ed in
PCa p og ession [141]. Thi d, choles e ol es e s a e abundan
componen s o lipid d ople s, whose p esence is associa ed wi h
PCa agg essi eness [148]. Gi en he ele ance o choles e ol
me abolism in cance , di e en he apeu ic s a egies ha e been
p oposed o PCa. S a ins a e choles e ol-lowe ing agen s ha a e
adminis e ed ch onically o millions o people a ound he globe.
Since hey inhibi HMGCR, hei po en ial an icance ac i i y has
been b oadly s udied [149]. In his ega d, high doses o s a ins
in i o consis en ly educe PCa agg essi eness [150,151].
Howe e , low doses o some o hese d ugs (equi alen o he
concen a ions eached in he blood o ea ed indi iduals) exhibi
pa adoxical e ec s on umou cells in i o and in i o [152]. This
disc epancy is e iden in epidemiological s udies moni o ing
he influence o s a in ea men in PCa pa hogenesis and
p og ession [149], sugges ing ha we s ill miss c i ical biological
in o ma ion ega ding how hese d ugs ope a e in cance .
Choles e ol me abolism could be pa icula ly ele an when
a ge ing and ogen p oduc ion o signalling in PCa. Indeed,
inhibi ion o squalene epoxidase (SQLE), a c ucial enzyme in
choles e ol biosyn hesis, has been p oposed as a p omising
pha macological in e en ion o ea ing CRPC [153,154]. Ta ge -
ing SQLE wi h e binafine e ec i ely inhibi ed o ho opic umou s
g ow h in mice. Mo eo e , in a clinical se ing, e binafine
demons a ed he abili y o dec ease p os a e-specific an igen
(PSA) le els in h ee ou o ou la e-s age p os a e cance pa ien s
[154]. Simila ly, he pha macologic blockade o SQLE wi h
FR194738 a enua ed he g ow h o PC3 cells bo h in i o and
in mouse xenog a models [153]. Finally, a complemen a y
s a egy o suppo and ogen syn hesis in condi ions o ho mone
dep i a ion is he p o ision o choles e ol by he TME. In his line,
mac ophages can se e as a sou ce o choles e ol o PCa cells in
he con ex o and ogen dep i a ion, hence suppo ing he
de elopmen o CRPC [155].
M. Pujana-Vaque izo e al.
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B i ish Jou nal o Cance (2024) 131:1250 – 1262

One-ca bon me abolism
One-ca bon (1 C) me abolism in ol es wo cen al cycles: he
ola e cycle and he me hionine cycle [156]. In he ola e cycle,
e ahyd o ola e (THF) ac s as a ca bon ca ie o pu ine and
hymidyla e syn hesis. Me hyl g oups ans e om 5-me hyl THF
o homocys eine, o ming me hionine and connec ing he wo
cycles. Me hionine is con e ed o S-adenosyl-me hionine (SAM), a
uni e sal me hyl dono o p o ein and DNA me hyla ion. SAM is
hen me abolized o S-adenosyl-homocys eine (SAH) and la e o
homocys eine, comple ing he cycle. Homocys eine p oduces
cys a hionine in he anssul u a ion pa hway, a p ecu so o
glu a hione. SAM can also eed in o he polyamine biosyn hesis
pa hway h ough i s deca boxyla ion by S-adenosylme hionine
deca boxylase (AMD1) [157] (Fig. 3). Al e a ions in 1 C me abolic
homeos asis a e a he co e o di e en diseases including cance
[156]. Tumou cells depend on 1 C me abolism o DNA syn hesis,
edox balance, me hyla ion eac ions and polyamine biosyn hesis.
All hese p ocesses a e ele an ac oss di e en cance s and
con ibu e o umou p og ession [158,159].
In PCa, and ogen signalling egula es he ac i i y o 1 C
enzymes in ol ed in SAM homeos asis, he anssul u a ion
pa hway and polyamine biosyn hesis [160]. In u n, changes in
AR ac i i y occu ing upon PCa p og ession and he apy can
influence 1 C me abolism and he in ica e epigene ic c oss alk
[160].
SAM homeos asis. GNMT and mi ochond ial SARDH a e c i ical
enzymes ha con ol SAM a ailabili y. They a e egula ed by
and ogen signalling and a e equen ly al e ed in PCa [161,162].
GNMT ans e s a me hyl g oup om SAM o glycine o o m SAH
and sa cosine, whe eas SARDH deme hyla es sa cosine o o m
glycine [163]. These wo eac ions de e mine he SAM:SAH a io
o he main enance o epigene ic esponses, and he p oduc ion
o sa cosine in his me abolic s ep has been p oposed as a
bioma ke in PCa, al hough his da a gene a ed in ensi e
con o e sy in he field [164,165]. GNMT, is epo ed o be bo h
up egula ed and down egula ed depending on he s udy, hus
sugges ing a mul i ac o ial egula ion in he di e en s ages o he
disease [166,167]. A easible explana ion ela es o egula ing
GNMT by signalling pa hways ha exhibi ecip ocal nega i e
eedback egula ion [168,169]. AR has a p edominan ole in
sus aining GNMT exp ession, whe eas PI3K ac i a ion induces i s
ep ession [170], a p ocess ha could depend on FOXO egula ion,
acco ding o s udies in D osophila melanogas e [171]. In e es -
ingly, Gnm le els a e p o oundly educed in P en loss-d i en
mu ine PCa, bu a ge mline dele ion o he me abolic enzyme
educed PCa incidence in his model, hus sugges ing ha ei he
esidual GNMT ac i i y is essen ial o umo igenesis o ha his
enzyme plays a c i ical ole in he TME [170]. Finally, a ecen s udy
has shown a mTORC1/ATF4-d i en down egula ion o p o ein
kinase C (PKC)
λ/ι
in neu oendoc ine p os a e cance ha inc eases
se ine biosyn hesis. This me abolic shi suppo s cell p oli e a ion
and ele a es in acellula SAM le els, p omo ing epigene ic
changes cha ac e is ic o his agg essi e o m o PCa [172].
The anssul u a ion pa hway. The anssul u a ion pa hway is a
b anch o 1 C me abolism ha con e s homocys eine o cys eine.
This p ocess in ol es se e al enzyma ic s eps, wi h cys a hionine
be a-syn hase (CBS) playing a p edominan ole [173]. CBS ac i i y
is con olled by SAM pools o di ec homocys eine owa ds
eme hyla ion when SAM le els a e low [173]. In PCa, s udies
showing bo h inc eased and dec eased exp ession o CBS ha e
been published [174,175]. Lowe enzyme le els a e ound in
me as a ic PCa cell lines, bu hese da a do no co ela e wi h
Cy
oplasm
Nucleus
3-PG
Se ine
Glycine
5,10-me hylene-THF THF
5-me hyl-THF
5- o myl-THF
Me hionine
DMG
Be aine
Homocys eine
SAM
SAH CH3
Cys a hionine
Cys eine GSH
Die
GLDC
MTHFR
MTR
Folic acid
DHFR
BHMT
MAT
SAHH
HMT
CBS
CTH
SSP
SHMT
Glycine
Sa cosine Sa cosine
Glycine
GNMT SARDH
dc-SAM
AMD1
A ginine
O ni hine
Spe mine
Pu escine
Spe midine
A ginase
ODC1
SRM
SMS
MTA
MTA
F
ola e c
y
cle
Me hionine c
y
cle
T
anssul u
a ion
pa hw
a
y
P
ol
y
amines pa hw
a
y
*
*
**
*
*
*
*
*
**
*AR esponsi e genes
Fig. 3 1 C me abolism in PCa. Main me aboli es and enzymes in ol ed in 1 C me abolism. This pa hway encompasses he ola e and
me hionine cycles, essen ial o cellula p ocesses like DNA syn hesis and me hyla ion. Addi ionally, i links o he anssul u a ion pa hway,
main aining edox powe h ough glu a hione syn hesis, and influencing ansla ion and p oli e a ion ia he polyamine biosyn hesis
pa hway. Red as e isks indica e AR- esponsi e enzymes desc ibed in he li e a u e. Abb e ia ions: 3-PG 3-phosphoglyce a e, THF
e ahyd o ola e, DMG dime hylglycine, SAM S-Adenosylme hionine, dc-SAM deca boxyla ed S-Adenosylme hionine, SAH S-adenosylhomo-
cys eine, MTA 5’-me hyl hioadenosine, GSH glu a hione. C ea ed wi h BioRende .com.
M. Pujana-Vaque izo e al.
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B i ish Jou nal o Cance (2024) 131:1250 – 1262
clinical e idence epo ing inc eased homocys eine and cys a hio-
nine abundance in pa ien s wi h wo se ou comes [176,177]. In
his line, cys ine deple ion sensi ises PCa cells o immune
checkpoin inhibi o s as well as o DNA damage-inducing agen s,
u he highligh ing he impo ance o hese in e media es in
PCa [178].
Polyamine biosyn hesis. Polyamines (PA) a e small polyca ions
essen ial o no mal cell g ow h in all euka yo ic o ganisms [179].
Pu escine is gene a ed om he u ea cycle h ough deca boxyla-
ion o o ni hine by o ni hine deca boxylase (ODC1), whe eas
AMD1 deca boxyla es SAM o dcSAM. This eac ion p o ides he
p opyl amines necessa y o o m spe midine and spe mine om
pu escine h ough he ac ion o spe midine syn hase (SRM) and
spe mine syn hase (SMS) [180]. The p os a e epi helium syn he-
sises high le els o polyamines ha a e sec e ed in o he seminal
fluid. And ogens con ol his p ocess h ough ansc ip ional
egula ion o ODC1 and AMD1 [181,182]. Acco dingly, and ogen
dep i a ion he apies educe he abundance o spe midine and
spe mine [183]. Howe e , egula ion o PA biosyn hesis in PCa
ex ends beyond AR signalling. On he one hand, ODC1 is a main
a ge o MYC, which associa es MYC amplifica ion and o e -
exp ession wi h ele a ed polyamine biosyn hesis [184]. The
egula ion o polyamine biosyn hesis downs eam MYC con i-
bu es o he umou supp essi e ac i i y o PGC1α, which was
ecen ly epo ed o ep ess his oncogene [185–187]. On he
o he hand, PI3K-mTORC1-dependen egula ion o AMD1 s abili y
influences polyamine syn hesis [188], an obse a ion ha is
ex ensible o o he pa hophysiological con ex s beyond
cance [189].
TUMOR CELL-EXTRINSIC METABOLIC INFLUENCES
P os a e cance is associa ed wi h ageing, and in u n, he
o ganism and cellula en i onmen ep esen an impo an
modifiable ac o in he pa hogenesis and p og ession o he
disease. The e is an eme ging in e es in s udying he me abolic
p ope ies o he umou mic oen i onmen , as well as how
exogenous ac o s like he die may impac umou p og ession.
The TME closely in e ac s wi h umou cells and comp ises
immune cells, fib oblas s, blood essels, and he ex acellula
ma ix [190]. Immune cells wi hin he TME can ei he igge p o-
umo al o an i- umo al esponses [191], while he ex acellula
ma ix and s omal cells wi hin he TME p o ide s uc u al and
biochemical suppo o umou s, influencing hei abili y o in ade
su ounding issues and me as asize [190]. Ad ances in high-
h oughpu , single-cell esolu ion echnologies ha e significan ly
enhanced ou comp ehension o cellula di e si y in PCa
[192–194]. Howe e , he e is s ill e y li le knowledge abou he
me abolic adap a ions in PCa s omal cells, and a glimpse a o he
umou ypes can p o ide c i ical in o ma ion on wha is o come
(Fig. 4).
Glucose me abolism in he TME
The ele a ed glycoly ic a e o umou cells is di ec ly esponsible
o c ea ing he acidic and nu ien -deple ed condi ions o he
TME, which ha e p o ound consequences o immune ac i i y
[195,196]. One o he mos significan e ec s o ae obic glycolysis
is he acidifica ion o he TME due o lac a e sec e ion [197,198],
which suppo s inc eased mig a ion and in asion [199] and
p omo es immune ep og amming owa ds a ole an pheno ype
[196,200]. Glycolysis in he umou s oma is also equi ed o
adequa e an i umo al esponse, which has led o he de elop-
men o me aboli e-based o mula ions in he p esence o a
glycoly ic inhibi o ha specifically a ge s cance cells [201].
Cance and T cells compe e o glucose among se e al o he
me aboli es, and he a idi y o cance cells o his nu ien
diminishes he cy oly ic ac i i y [195,202,203]. Glycoly ic
capaci y in T cells is also influenced by oncome aboli es such
as 2-hyd oxyglu a a e, which is p oduced a high concen a ions
in isoci a e dehyd ogenase mu an cance s and inhibi s hei
p oli e a ion, cy okine p oduc ion, and abili y o kill umou
cells [204].
Lipid me abolism in he TME
Lipid me abolism is simila ly equi ed in s omal cells. SREBP
ac i i y o ches a es he immune esponses in cance . Inhibi ion o
SREBP unc ion in egula o y T cells (T eg) enhances an i umou
immune esponses [205]. Pa icula ly, SREBP-clea age-ac i a ing
p o ein dele ion in in a- umo al T egs inhibi s umou g ow h and
imp o es PD-1- igge ed immuno he apy by egula ing
in e e on-γp oduc ion [205]. Simila ly, dele ion o FABP5 in T eg
a ec s mi ochond ial in eg i y and igge s cGAS-STING-
dependen ype I IFN signalling [206]. Mac ophages a e egula ed
by umou cells a mul iple le els and hei pola isa ion
con ibu es o he acquisi ion o agg essi e ea u es. Up egula ion
o CD36 in me as asis-associa ed mac ophages (MAMs) p omo es
umou cell-de i ed a y acid up ake, p o umou al pola iza ion
and hei suppo i e ole in he es ablishmen o li e me as asis
[207]. Thus, a ge ing CD36 eme ges as a wo-hi s a egy
a ge ing bo h umou and immune cells in he ea men o
me as asis. Lipids can also suppo he ac i a ion o lymphocy es.
As an illus a i e example, linoleic acid ac i a es CD8 +T cells,
enhancing me abolic fi ness and p e en ing exhaus ion [208],
highligh ing i s ole as a po en ial adju an o po en ia e adop i e
T cell he apy.
One-ca bon me abolism in he TME
Ve y li le is known abou he con ibu ion o 1 C me abolism o
he TME in PCa. In u n, sca e ed e idence in o he umou ypes
can p o ide an idea o he p ocesses influenced by his me abolic
ou e in cance . Deficiencies in one-ca bon me abolism impai he
e ec i eness o PD-1 blockade in melanoma. Cohe en ly, aug-
men ing 1 C me abolism h ough o ma e supplemen a ion
du ing an i-PD-1 he apy imp o es CD8 +T-cell fi ness and
acili a es CD8 +T-cell-media ed umou clea ance [209]. These
esul s indica e ha o ma e supplemen a ion has he po en ial o
enhance he unc ion o exhaus ed CD8 +T cells. Impo an ly, he
acidifica ion o he ex acellula milieu also influences T cell
unc ion, elici ing a educ ion in me hionine me abolism ia
SLC7A5 down egula ion ha esul s in a ‘s em-like memo y’s a e.
This ep og amming enhances T cell pe sis ence and an i- umou
e ficacy in mice, e ealing a no el influence o acidic condi ions on
T cell cha ac e is ics [210]. The ele ance o 1 C me abolism o
glu a hione p oduc ion and edox balance is an addi ional ac o
con olling he ac i i y o he TME. Dis up ing glu a hione
syn hesis in T egs impai s hei abili y o egula e se ine
me abolism, leading o se e e au oimmuni y and imp o ed an i-
umou esponses [211]. Tumou -in insic 1 C me abolism p o-
duces sec e ed me abolic in e media es ha can emodel he
TME. Tumou cells exhibi equen loss o me hyl hioadenosine
phospho ylase (MTAP), which leads o he accumula ion o i s
subs a e MTA [212]. Sec e ed MTA is up aken and me abolized by
fib oblas s, which will p oduce and sec e e bo h pu ine p oduc s
and cy okines ha induce mac ophage pola iza ion.
Die and obesi y
Nu i ion ep esen s he igh es in e ac ion o ou o ganism wi h
he en i onmen . As such, i is closely linked o he de elopmen
o diseases, including cance . S udies in o he umou ypes ha e
un eiled addi ional molecula p ocesses esponsible o he high-
a die -induced pheno ype. In o al ca cinoma and melanoma
models die a y palmi ic acid, bu no oleic o linoleic acid,
p omo es me as asis in mice [139,140]. Molecula ly, palmi ic acid
induces a p o-me as a ic memo y in ol ing CD36, his one
modifica ions, and a neu al signa u e linked o Schwann cells,
M. Pujana-Vaque izo e al.
1256
B i ish Jou nal o Cance (2024) 131:1250 – 1262
leading o bo h me as asis ini ia ion and long- e m me as a ic
memo y. These same modifica ions may also play a ole in PCa
[140]. In line wi h he ole o CD36, a high- a die has been shown
o p omo e me as asis by enhancing sa u a ed a y acid up ake
ia his ecep o in b eas cance [213]. Modifica ions in die a y
habi s could also be beneficial o cance pa ien s. Calo ic
es ic ion induces an i-p oli e a i e e ec s in mouse xenog a s,
an e ec ha is limi ed o umou s wi hou mu a ions causing
cons i u i e ac i a ion o he PI3K pa hway [214]. Mo e ecen ly,
calo ic es ic ion has been shown o inhibi he g ow h o ce ain
umou s in mice by lowe ing lipid le els in bo h plasma and
umou s [215]. This die a y modifica ion educes s ea oyl-CoA
desa u ase ac i i y in cance cells, causing an imbalance be ween
unsa u a ed and sa u a ed a y acids and impai ing umou
g ow h.
In PCa obesi y has been linked o an inc eased isk and
p og ession o he disease in epidemiological s udies [216–218],
owing o he con ibu ion o ac o s such as insulin esis ance,
ch onic inflamma ion, o ho monal dys egula ion, among o he s.
Howe e , he causal con ibu ion o obesi y o PCa and he
mechanis ic ounda ions o his e ec emains elusi e. Mu ine
models ha e shed some ligh on hese ques ions. Obesi y and
high calo ie-induced hype insulinemia p omo e PCa in p os a e-
specificP en
-/-
mice by inc easing cell p oli e a ion and ac i a ing
insulin/IGF1/PI3K/AKT signalling pa hways [219,220]. In line wi h
his no ion, mu a ions in PCa ha ac i a e PI3K (such as p os a e-
specificP en loss) p ime o p omo e obesi y-d i en PCa agg es-
si eness in conjunc ion wi h o he signalling pa hways, such as
loss o P pn1 [221], IL6/pSTAT3 signalling ac i a ion [222]o Pml
co-dele ion [223]. This knowledge o e s new he apeu ic oppo -
uni ies o a ge ing PTP1B, IL6 o PML-loss induced SREBP
signalling in he con ex o obesi y.
Al hough much o he emphasis on he influence o obesi y has
been pu on lipid a ailabili y and ch onic inflamma ion, suga s could
also play a ele an ole. Indeed, inc eased exp ession o uc ose
anspo e s in PCa has been sugges ed o p omo e uc ose up ake
and me abolism o suppo cance cell fi ness [224].
Collec i ely, die a y in e en ions may also play a ole in bo h
he p og ession and ea men o PCa, and u he s udies a e
equi ed o ex end he knowledge o molecula and biological
e ec o s ha can be ansla ed in o p e en i e and he apeu ic
ac ions.
Tumo al
cell
Immune ole ance
Lac a e
Lac a e
In asion
Neu ophil
Mac ophage
Dend i ic
cell
T-Cell
SCAP o FABP5
dele ion
T-Cell
Enhanced
immuno he apy
e ec i i y
Mac ophage
CD36
up egula ion
Me as asis
+
immunosup ession
FA
Enhanced immune
e ec i i y
T-Cell
Linoleic
acid
GSH inhibi ion
Fo ma e
IDH
mu an s
2-HG
T-Cell
Reduced immune
e ec i i y
Fib oblas
MTAP
dele ion
MTA
Pu ines
+
Cy okines
Mac ophage pola iza ion
Die in e en ions
Obesi y
P en/PTP1B/IL6/PML
dele ion
Palmi ic acid
Me as asis
F uc ose in ake
Calo ic es ic ion
P oli e a ion
Tumo al
Cell
Na u al
kille cell
Fig. 4 The ole o me abolism in he cance umou mic oen i onmen . Summa y o he ecen concep s ega ding he in e ac ion o
umou me abolism wi h he umou mic oen i onmen o suppo cance p og ession. Abb e ia ions: 2-HG 2-Hyd oxyglu a a e, GSH
glu a hione, IDH isoci a e dehyd ogenase, MTAP S-me hyl-5’- hioadenosine phospho ylase, MTA 5′-deoxy-5′-me hyl hioadenosine. C ea ed
wi h BioRende .com.
M. Pujana-Vaque izo e al.
1257
B i ish Jou nal o Cance (2024) 131:1250 – 1262
CONCLUDING REMARKS AND OPEN QUESTIONS
O e he pas decade, he e ha e been ex ensi e e o s o
unde s and he mechanisms and biological consequences o
me abolic ep og amming in cance . Al hough cu en ly he e a e
no d ugs app o ed o PCa ea men ha a ge specific
me abolic pa hways, he e a e mul iple agen s in de elopmen .
Me abolic ep og amming is essen ial o he biology o cance
cells. Tumou me abolism is influenced by cance cell-specific
me abolic adap a ions as well as by me abolic al e a ions in he
TME. Mode n echnologies o s udy me abolism, including new
imaging echniques, spa ial me abolomics and single-cell RNA
sequencing ha e edefined ou knowledge o cance me abolism.
Howe e , despi e ex ensi e esea ch in PCa me abolism, he e is
s ill a gap in knowledge on he he apeu ically-ac ionable
me abolic pa hways ha a e ele an o each s age o he disease.
Fu he esea ch in o he me abolic dependencies o he p ima y
umou and hose o he me as a ic lesions, including he ole o
e op osis, hypoxia and mic obio a, migh lead o new me abolic
in e en ions o p e en me as a ic dissemina ion o p os a e
cance , and o significan imp o emen s in he cu a ion a e o his
disease.
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