7
V-ATPase Inhibi o s in Cance T ea men and
Thei Implica ion in Mul id ug Resis ance
in O al Squamous Cell Ca cinoma
Ma io Pé ez-Sayáns and Abel Ga cía Ga cía
Uni e si y o San iago de Compos ela
Spain
1. In oduc ion
ATPases a e enzyme sys ems ha o igina ed in a common ances o and a e dis ibu ed
uni e sally among all o ganisms. The e a e h ee ypes o ATPases: hose ound in a chaea
(A-ATPases), syn hases (F-APTases), and acuole o acuola ATPases (V-ATPases)
(Nelson, Nelson 1989). They a e essen ial o li e and ha e in common he ac ha hey
c ea e an elec ochemical ion g adien ac oss he memb ane o hyd olyze o syn hesize ATP.
S uc u ally, hey a e enzyma ic complexes ha wo k as molecula o a y mo o s. ATPases
a e o med by wo domains, a hyd ophobic domain (A0, V0, and F0) and a hyd ophilic
domain (A1, V1, and F1) connec ed by a cen al axis and ei he one o wo la e al axes. In
his chap e , we a e going o discuss V-ATPases.
1.1 Biological unc ions
Unlike F-ATPases, whose p ima y unc ion in euka yo ic cells is o gene a e ATP om
p o on mo i e o ce, V-ATPases unc ion exclusi ely as ATP-dependen p o on pumps,
pe o ming di e se biological unc ions wi hin cells (Nelson 1992; Kane 1999; Sa oussi &
Nelson 2008, S e ens & Fo gac 1997).
Rega ding o he memb ane anspo , V-ATPases play an impo an ole in ecep o -
media ed endocy osis (Fo gac 1998), in acellula anspo , and he acidi ica ion o la e
endosomes (Kane 1999; S e ens & Fo gac 1997; Nishi & Fo gac 2002; Kawasaki-Nishi &
Fo gac 2003; Finbow, Ha ison 1997). Vacuola acidi ica ion has also been epo ed o be
in ol ed in he anspo o lysosomal enzymes om he Golgi appa a us o he lysosomes
(S e ens, Fo gac 1997; Mo iyama, Nelson 1989). V-ATPases appea o play an impo an ole
in he c ea ion o he mic oen i onmen needed o co ec p o ein anspo , exchange, and
sec e ion (Schoonde woe e al. 2000).
Al hough V-ATPases we e ini ially iden i ied in in acellula compa men s, knowledge on
he oles hey play in he plasma memb ane has inc eased eno mously. V-ATPases loca ed
a he apical memb ane o ype A in e cala ed cells a e in ol ed in he sec e ion o p o ons
in enal luid (Smi h e al. 2005; an Hille e al. 1993). Type B in e cala ed cells, whose
unc ion is o sec e e bica bona e, also con ain V-ATPases, bu hey a e loca ed be ween he
apical and basola e al memb anes (Nishi & Fo gac 2002, an Hille e al. 1993). In
mac ophages and neu ophils, plasma memb ane V-ATPases (pmV-ATPases) a e in ol ed
Cu en Cance T ea men – No el Beyond Con en ional App oaches
130
in he homeos asis o cy oplasmic pH (S e ens & Fo gac 1997, Nishi & Fo gac 2002, Nanda
e al. 1996). These ATPases also play an impo an ole in bone eabso p ion (Ma shansky,
Fu ai , S e ens, Fo gac 1997, Nishi, Fo gac 2002, Smi h e al. 2005, an Hille e al. 1993).
Ano he o hei unc ions is o egula e spe m mo ili y and ma u a ion on he apical
memb ane o epididymal cells and as de e ens by s abilizing he spe m medium (Nishi,
Fo gac 2002). The ole o V-ATPases in cance cells will be discussed in a speci ic place.
O he addi ional unc ions o V-ATPases in ol es he low pH main ained by hem in
lysosomes and phagosomes, which is necessa y o he ac i i y o he deg ada i e enzymes
in hese compa men s (Sun-Wada, Wada & Fu ai 2003, Sun-Wada, Wada & Fu ai 2004,
Ku ashima e al. 1996) and he anspo o small molecules and ions (Nishi, Fo gac 2002,
Ku ashima e al. 1996). The d i ing o ce necessa y o he accumula ion o
neu o ansmi e s in synap ic esicles is p o on mo i e o ce, which is gene a ed by V-
ATPases (Nelson, Ha ey 1999). The usion- ission balance o he acuola sys em o
euka yo ic cells is also con olled by V-ATPases, i.e. ia he in e ac ion be ween acuola
SNARE p o eins and GTPase Vps1p (Baa s e al. 2007, Mulle e al. 2003). Exocy osis in
eosinophils and binding o ac in cy oskele on is also egula ed by V-ATPases (Ku ashima e
al. 1996). The associa ion be ween V-ATPase subuni s and o he cellula p o eins, o
example, ha which occu s be ween he C subuni o he V0 domain and he E5
oncop o ein, o be ween pla ele -de i ed g ow h ac o (PDGF) and b1 in eg in, indica e
ha hese subuni s play a ole in cell g ow h and ans o ma ion. V-ATPases also allow he
en y o ce ain i uses (e.g. in luenza) and oxins (e.g. diph he ia) in o he in acellula
space ia he binding o hese pa hogens o he endosomal memb ane (S e ens, Fo gac
1997). In he case o he human immunode iciency i us (HIV), he associa ion be ween he
V-ATPase H subuni and he HIV-1 Ne p o ein, which con ols he exp ession o CD4 ( he
main HIV ecep o ), acili a es endocy osis o Ne and/o al e a ions in he acidi ica ion o
he endosomal pa hway by his p o ein (Nishi, Fo gac 2002)(Ma shansky, Fu ai ). The mos
ecen unc ion a ibu ed o V-ATPases is hei in ol emen in he egula ion o cell-cell
usion o o m la ge cells, as is he case wi h os eoclas s and mac ophages (Wada e al.
2008).
1.2 V-a pase s uc u e
The V-ATPase p o on pump has mul iple subuni s, each wi h mul iple iso o ms, hence he
need o a clea , s anda dized nomencla u e sys em. Ini ially, he HUGO Gene
Nomencla u e Commi ee ag eed o use he ATP as he s em, o oo , symbol. ATP6, o
example, indica ed ATPase, H+ anspo , lysosomal ( acuola p o on pump). In 2003, he
nomencla u e sys em o genes encoding V-ATPase subuni s was e ised and i was decided
o main ain he oo ATP6 and add he domain o which a pa icula subuni belonged,
ollowed by he le e o he subuni , and inally he numbe o he iso o m, whe e ele an ,
(e.g. ATP6V1C1, ATP6V1E, e c.) (Smi h A.N. e al. 2003).
V-ATPase s uc u e, unc ion, biogenesis, and egula ion was widely e ised by S e ens and
Fo gac (S e ens & Fo gac 1997). We will use he nomencla u e sys em p oposed by hese
au ho s o explain he s uc u al subuni s o V-ATPase oge he wi h ele an modi ica ions
based on ecen esea ch using ansmission elec on mic oscopy (Wilkens, Zhang & Zheng
2005).
V-ATPases ha e been ound o be p ac ically iden ical in e ms o he composi ion o hei
subuni s in all euka yo ic cells. They ha e wo dis inc s uc u es: a pe iphe al ca aly ic

V-ATPase Inhibi o s in Cance T ea men and Thei
Implica ion in Mul id ug Resis ance in O al Squamous Cell Ca cinoma
131
sec o (V1) and a hyd ophobic memb ane sec o (V0) esponsible o d i ing p o ons
(G ube 2005). The ca aly ic sec o is composed o i e polypep ides known as subuni s A, B,
C, D, and E, wi h a molecula weigh , in dec easing o de , anging om 72 o 33 kDa. Recen
ad ances in knowledge o he mechanism o ac ion o F-ATPases ha e cla i ied he
ela ionship be ween unc ion and s uc u e o each o he subuni s o hese enzymes (Qi,
Wang & Fo gac 2007, Inoue e al. 2005) (Figu e 1).
Fig. 1. Diag am o V-ATPase. The cy osolic domain (in yellow) is o med by h ee A
subuni s, h ee B subuni s, h ee G subuni s, and one C, D, E, F, and H subuni . The V0
ansmemb ane domain is o med by i e subuni s: a, c, c’, c’’ and d. The V1 domain
con ains he ca aly ic uni (Nishi & Fo gac 2002).
1.3 V-ATPase egula ion
Th ee majo egula o y mechanisms ha e been desc ibed o V-ATPase: 1) he egula ion o
pump densi y, which allows di e en cells o main ain hei cy oplasmic and acuola pH
s able; 2) he egula ion o V1 and V0 domain associa ion/dissocia ion, o example, a
dec ease in glucose le els can cause a 70% dissocia ion o he V1 domains o he memb ane;
and 3) he egula ion o sec e o y ac i i y, ia he main enance o balance in he o ma ion o
bisul i e and binding e iciency be ween H+ and he pump. O he mechanisms include he
necessa y modi ica ions in he memb ane po en ial o he gene a ion o elec ogenic o ce
(Fo gac 1998; Peng, S one & Xie 1993) and al e a ions in he acuola anspo e chape one
(V c) complex, which a ec he con o ma ion o he V0 domain and i s unc ion in acuole
usion o he memb ane (Mulle e al. 2003).
Cu en Cance T ea men – No el Beyond Con en ional App oaches
132
2. V-ATPase inhibi o s
Scien i ic e idence sugges s ha he acidic umo mic oen i onmen is key o managing
cance p og ession and me as asis. In pa icula , V-ATPases play a majo ole in me as asis
umo de elopmen because many umo cells sec e e lysosomal enzymes ha pa icipa e in
he ex acellula ma ix deg ada ion necessa y o me as a ic in asion. These enzymes a e
mos ac i e a low op imal pH; mo eo e , V-ATPases a e esponsible o mic oen i onmen
acidi ica ion (Nishi, Fo gac 2002, Ma inez-Zaguilan e al. 1993). Among he many
mechanisms ha egula e he umo mic oen i onmen , V-ATPases a e especially
signi ican because hey can be inhibi ed by p o on pump inhibi o s. (Fais e al. 2007).
2.1 Classes o V-ATPase inhibi o s
Ini ial a emp s o block V-ATPases we e made a e ba ilomycin and concanamycin we e
disco e ed in 1988 (Bowman, Siebe s & Al endo 1988). New molecules capable o
inhibi ing V-ATPase o a g ea e o lesse ex en ia di e en mechanisms o ac ion we e
la e disco e ed. Such molecules include benzolac one enamides salicylihalamide (E ickson
e al. 1997), loba amide A and B (Galinis e al. 1997), apicula en (Kunze B., Janse R., Sasse F.,
Hö le G. and Reichenbach H. 1998), indolyls (Gaglia di e al. 1998, Nadle e al. 1998),
oximidine (Kim e al. 1999), mac olac one a chazolid (Sasse e al. 2003), loba amide C (Shen
e al. 2003), and c uen a en(Kunze e al. 2006). The la es gene a ion o inhibi o s include
NiK12192 (Sa oussi, Nelson 2008, Pe angolini e al. 2006), FR202126 (Niiku a 2007), and PPI
SB 242784 (Hesselink e al. 2008). We can see he di e ences and simila i ies o V-ATPase
inhibi o s in Table 1:
The V-ATPase inhibi o s s udied mos ho oughly and used mos o en a e mac olide
an ibio ics wi h 18-membe ed lac one ings, namely, ba ilomycins and concanamycins.
Ba ilomycin and concanamycin a e comme cially a ailable, and a ious labo a o ies ha e
de eloped in i o syn hesis p ocesses o expe imen al pu poses (Scheid e al. 2002). The
emaining V-ATPase inhibi o s a e s ill in expe imen al phase, due o possible side e ec s
ha may occu in humans. Howe e , PPIs a e he ea men o choice o pep ic diseases
such as gas oesophageal e lux (La sson e al. 1985). While hese pumps block he sec e ion
o gas ic acid, hey also di ec ly inhibi V-ATPase ac i i y. Examples o PPIs include
omep azole, esomep azole, lansop azole, pan op azole, and abep azole (Ho n 2000), all o
which accumula e in acidic compa men s (De Mili o, Fais 2005a). PPI ea men has been
associa ed wi h V-ATPase ac i i y inhibi ion and an inc ease in bo h ex acellula pH and
pH in lysosomal o ganelles. In i o expe imen s using mice/human xenog a s ha e shown
ha p e ea men wi h PPIs can sensi ize solid human umo s o chemo he apy d ugs (De
Mili o, Fais 2005a).
T ea men wi h PPIs has also been ound o sensi ize umo cells o cispla in, 5- luo acil, and
inblas ine h ough changes in cellula pH g adien s, wi h e en ion o he d ugs in he
cy oplasm, and in he nucleus in he case o doxo ubicin (De Mili o, Fais 2005a, Luciani e al.
2004, Luciani e al. 2004, Cian iglia e al. 1990).
I is also known ha low pH le els a e sui able o he comple e ac i a ion o PPIs (De Mili o
e al. 2007), sugges ing ha umo alkaliniza ion may be an ex emely in e es ing a ge o
u u e an icance ea men s (De Mili o, Fais 2005a, Luciani e al. 2004, De Mili o, Fais
2005b). Speci ic V-ATPase inhibi o s such as concanamycin and ba ilomycins a e o he
candida es o in es iga ion, no only o ea cance bu also o educe MDR in umo s
(Pe ez-Sayans e al. 2009, Sasazawa e al. 2009).
V-ATPase Inhibi o s in Cance T ea men and Thei
Implica ion in Mul id ug Resis ance in O al Squamous Cell Ca cinoma
133
CLASSES OF V-ATPase INHIBITORS
Chemis y P o enience Binding si e Ac ion
Plecomac olide
Concanamycin
&
Ba ilomycin
Mac olide
an ibio ics
wi h 18-
membe ed
lac one ings
S ep omyces
Unknown
V-ATPases
inhibi ion
Ionopho ic
p ope ies
Benzolac one enamides
Salicylihamide
A
Apicula ens
Loba amides
Oximidines
C uen a en
Mac ocyclic
salicyla e
Sponge Haliclona
sp.
VO complex Animal V-ATPases
inhibi ion
Cy o oxin
Lac one ing Chond omyces VO complex Highly oxic o
human and animal
cell
Subs i u ion o
enamide NH,
salicyla e, and
phenyl salicyla e
Tunica e Aplidium
loba um
VO complex
Animal and
mammalian V-
ATPases inhibi ion
Lac one ing Pseudomonas sp. VO complex Animal and
mammalian V-
ATPases inhibi ion
Lac one ing Bysso o ax c uen a VO complex Cy o oxici y on
mammalian and
ungal cells a
mi ochond ial F-
ATPases
A chazolid Mac ocyclic
lac one ing
wi h a hiazole
side
A changium
gephy a
Cys obac e
iolaceus
VO subuni c Cy o oxici y on
mammalian cell line
Indolyls Ba ilomycin-
based
Syn hesis VO subuni c V-ATPase inhibi o
La e-gene a ion
V-ATPase
inhibi o s
NiK12192, SB 242784, FR202126, 3-b omopy u a e (3-B PA),
T ibu yl in chlo ide (TBTCl), FR177995, FR167356
Table 1. Classes o V-ATPase inhibi o s
3. Role o -ATPases inhibi o s in cance
3.1 Tumo me as asis
The de elopmen and main enance o he p o on g adien p esen in umo s is due di ec ly o
he abili y o umo cells o sec e e p o ons (H+) (Ma inez-Zaguilan e al. 1993, McLean e al.
2000), acidi y he ex acellula medium (Ca done, Casa ola & Reshkin 2005, Pe ona, Se ano
1988), and keep he cy osolic pH alkaline (Sennoune, Ma inez-Zaguilan 2007). This abili y also
Cu en Cance T ea men – No el Beyond Con en ional App oaches
134
inc eases wi h umo agg essi eness (Mon cou ie e al. 1997, Pa kins e al. 1997). In addi ion,
low pH may cause ex acellula ma ix (ECM) deg ada ion and emodeling h ough ac i a ion
o p o eoly ic enzymes which con ibu e o in asion and cance me as asis (Ma inez-Zaguilan
e al. 1996, Ro s ad e al. 2006). P o eases need low ex acellula pH o op imize hei
ac i a ion, including me allop o einases (MMP), mo phogene ic bone me allop o einases
(p o ein ype 1), issue se ine p o eases, and adamalysin- ela ed p o einases. Among hem,
MMPs a e he p o eases basically in ol ed in deg ada ion and emodelling o all ex acellula
ma ix (ECM) s uc u al componen s (Mon cou ie e al. 1994, Rozhin e al. 1994, Johnson e
al. 2000, Ka o e al. 2005, Goche a, Joyce 2007).
Sennoune e al. assessed he e ec o ba ilomycin A1 in b eas umo cells and ound ha
cy oplasmic pH eco e y was inhibi ed in esponse o acid load, in bo h highly and lowly
me as a ic cells, al hough o a g ea e ex en in highly me as a ic cells (Sennoune e al. 2004).
This sugges s ha V-ATPases in he plasma memb ane a e in ol ed in he acquisi ion o a
mo e me as a ic pheno ype and ha he use o V-ATPase inhibi o s allows dis an
me as asis o be minimized (Figu e 2).
Fig. 2. P oposed mechanism by which o e exp ession o pmVATPase a he leading edge o
he cell modula es cell mig a ion/in asion. The p oposed model should be iewed as a
amewo k o explain how pmV-ATPases de e mine he acquisi ion o an in asi e
pheno ype needed o angiogenesis and me as asis. Changes in pHcy a e c i ical o
es ablishing cell pola i y needed o cell mo emen . A c i ical s ep in di ec ed mo ili y and
mig a ion is he asymme ic ac in polyme iza ion a he leading edge (Sennoune, Ma inez-
Zaguilan 2007).
V-ATPase Inhibi o s in Cance T ea men and Thei
Implica ion in Mul id ug Resis ance in O al Squamous Cell Ca cinoma
141
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