CIRCUITOS INTEGRADOS EN CANCER

METABOLISMO Y CNCER

METABOLISMO ENERGETICO DEREGULADO

Glucosa, insulina, metabolismo y cncer

La insulina es un factor de crecimiento

BANTING Y BEST (TO ONTO, !"#!$ BANTING Y %A&LEO', ( E%IO NOBEL 'E %E'I&INA, !"#)

A fin de *rote+er su *ri, acidad, (o-er(oint blo.ue/ la descar+a automtica de esta ima+en0

GL5T 6

GLUT 4

Tyrosine 1inase rece*tors, includin+ t2e insulin receptor, mediate t2eir acti,ity by causin+ t2e addition of a *2os*2ate +rou* to *articular tyrosine residues on certain *roteins -it2in a cell0 T2e 3substrate3 *roteins t2at are *2os*2orylated by t2e Insulin rece*tor include a *rotein called 3I S4!3 for 3insulin rece*tor substrate !30 I S ! bindin+ and *2os*2orylation e,entually leads to an increase in t2e 2i+2 affinity GL5T6 (Glucose trans*orter 6$ molecules on t2e outer membrane of insulin4res*onsi,e tissues, includin+ %yocytes and Adi*ocytes0 T2us t2ere is an increase in t2e u*ta1e of Glucose molecules from blood into t2ese cells0 T2e +lucose trans*orter GL5T6 is trans*orted from cellular ,esicles to t2e cell surface, -2ere it t2en can mediate t2e trans*ort of +lucose into t2e cell0

GL5&OSA

A&I'O (I 57I&O

A&I'O LA&TI&O

CICLO DE KREBS

ISTA GENERAL Y GLOBAL DE LA !RODUCCION DE ENERGIA

LA&TATO

SE &ONS5%EN # AT(s SE ( O'5&EN 6 AT(s BALAN&E NETO # AT(s

El ciclo de 8rebs y la cadena res*iratoria *roducen )9 AT(s

La cadena de trans*orte de electrones

La cadena de trans*orte de electrones

# :; ; # e ; !<# O# 444= :#O ; ener+y

BALANCE ENERGETICO

> El efecto ?arbur+

Otto "#r$ur%& !re'io No$el (e )isiolo%*# +,-+

IMAGEN DE CEREBRO EN !ET SCAN

!ET SCAN DE LIN)OMA ANTES Y DES!UES TRATAMIENTO .)DG/

@i+ure !0 T0e Altere( Met#$olis' o1 C#ncer Cells Dri2ers .A #n( B/& T0e 'et#$olic (er#n%e'ents in c#ncer cells '#3 #rise eit0er 1ro' t0e selection o1 cells t0#t 0#2e #(#pte( to t0e tu'or 'icroen2iron'ent or 1ro' #$err#nt si%n#lin% (ue to onco%ene #cti2#tion& T0e tu'or 'icroen2iron'ent is sp#ti#ll3 #n( te'por#ll3 0etero%eneous4 cont#inin% re%ions o1 lo5 o63%en #n( lo5 p7 .purple/& Moreo2er4 '#n3 c#nonic#l c#ncer8#ssoci#te( si%n#lin% p#t05#3s in(uce 'et#$olic repro%r#''in%& T#r%et %enes #cti2#te( $3 03po6i#8in(uci$le 1#ctor .7I)/ (ecre#se t0e (epen(ence o1 t0e cell on o63%en4 50ere#s R#s4 M3c4 #n( A9t c#n #lso upre%ul#te %lucose consu'ption #n( %l3col3sis& Loss o1 p:- '#3 #lso rec#pitul#te t0e 1e#tures o1 t0e "#r$ur% e11ect4 t0#t is4 t0e uncouplin% o1 %l3col3sis 1ro' o63%en le2els&A(2#nt#%es .C;E/& T0e #ltere( 'et#$olis' o1 c#ncer cells is li9el3 to i'$ue t0e' 5it0 se2er#l proli1er#ti2e #n( sur2i2#l #(2#nt#%es4 suc0 #s en#$lin% c#ncer cells to e6ecute t0e $ios3nt0esis o1 '#cro'olecules .C/4 to #2oi( #poptosis .D/4 #n( to en%#%e in loc#l 'et#$olite8$#se( p#r#crine #n( #utocrine si%n#lin% .E/&!otenti#l Li#$ilities .) #n( G/& T0is #ltere( 'et#$olis'4 0o5e2er4 '#3 #lso con1er se2er#l 2ulner#$ilities on c#ncer cells& )or e6#'ple4 #n upre%ul#te( 'et#$olis' '#3 result in t0e $uil( up o1 to6ic 'et#$olites4 inclu(in% l#ct#te #n( nonc#nonic#l nucleoti(es4 50ic0 'ust $e (ispose( o1 .)/& Moreo2er4 c#ncer cells '#3 #lso e60i$it # 0i%0 ener%etic (e'#n(4 1or 50ic0 t0e3 'ust eit0er incre#se 1lu6 t0rou%0 nor'#l AT!8%ener#tin% processes4 or else rel3 on #n incre#se( (i2ersit3 o1 1uel sources .G/&

Glucose metabolism in cancer

AEl cncer es tontoB

C A(or.uD una cDlula tumoral, .ue tiene +randes re.uerimientos de ener+Ea *rioriFa la ,Ea de la +luc/lisis aerobia .ue solo *roduce # AT(s, en lu+ar de la ,Ea de la fosforilaci/n oGidati,a .ue *roduce )9 AT(sB

Ensayaremos una res*uesta

> El cncer no es tonto0 > Adems de ener+Ea, la cDlula tumoral re.uiere > >
tambiDn muc2as otras sustancias *ara elaborar cidos +rasos, *roteEnas y ribosa fosforilada0 Estas sustancias se elaboran a *artir del cido lctico, eGce*to la ribosa0 (or otro lado, no se *roduce dDficit ener+Dtico *or.ue la cDlula tumoral metaboliFa !H ,eces ms molDculas de +lucosa en la unidad de tiem*o .ue la cDlula no tumoral0

El Efecto ?arbur+ es mal entendido

M& G& #n(er 7ei(en et #l& #((resse( t0e <uestion o1 503 # cell 5oul( =c0oose= %l3col3sis o2er o6i(#ti2e p0osp0or3l#tion4 50ere$3 onl3 > inste#( o1 -? #(enosine :@8trip0osp0#te .AT!/ #re o$t#ine( per %lucose 'olecule .=Un(erst#n(in% t0e "#r$ur% E11ectA T0e 'et#$olic re<uire'ents o1 cell proli1er#tion4= Re2ie5s4 >> M#3 >BB,4 p& +B>,/& 7o5e2er4 t0e <uestion4 #s 5ell #s t0e pro11ere( e6pl#n#tions4 'isses t0e point o1 "#r$ur%@s 5or9& In +,>- #n( +,>44 "#r$ur% #n( co85or9ers reporte( t0#t t0e r#te o1 respir#tion in c#ncer cells is4 5it0in t0e error4 i(entic#l to t0#t o1 nor'#l cells4 #n( t0#t t0e %lucose upt#9e is #ppro6i'#tel3 +B ti'es 0i%0er& )urt0er'ore4 1or e2er3 +- %lucose 'olecules t#9en up4 + is o6i(iCe( 2i# respir#tion4 50ile t0e re'#inin% +> #re split to 1or' l#ctic #ci( .+4 >/& T0us4 in t0e ti'e t0#t one %lucose 'olecule pro(uces -? AT! 2i# respir#tion4 >4 #((ition#l AT! #re %ener#te( 2i# #ero$ic %l3col3sis& T0e <uestion pose( $3 #n(er 7ei(en et #l&4 =503 (o proli1er#tin% cells s5itc0 to # less e11icient 'et#$olis'= is 5ron% on t5o countsA .i/ c#ncer cells (o not s5itc04 $ut c#rr3 out $ot0 o6i(#ti2e p0osp0or3l#tion #n( #ero$ic %l3col3sis si'ult#neousl34 #n( .ii/ %l3col3sis is not ine11icientD e2en in t0e #$sence o1 o63%en4 c#ncer cells sur2i2e $ec#use l#ctic #ci( pro(uction 2i# #n#ero$ic %l3col3sis 3iel(s >E- o1 t0e AT! t0#t # nor'#l cell pro(uces $3 respir#tion& In(ee(4 it is precisel3 t0is enor'ous upt#9e o1 %lucose t0#t #llo5s c#ncerous tissue to $e 2isu#liCe( $3 )DG8!ETECT& T0e <uestion o1 50et0er or not c#ncer cells respire nor'#ll3 0#s (o%%e( t0e liter#ture since t0e l#te +,>Bs& E6peri'ent#l results o1 "#r$ur% #n( co85or9ers #n( o1 C0#nce #n( co85or9ers .-4 4/ cle#rl3 s0o5 t0#t respir#tion is nor'#l& "03 t0en (i( "#r$ur% 0i'sel1 in +,:? 5rite t0#t =Ft0e respir#tion o1 #ll c#ncer cells is (#'#%e(&&&= .:/G "#r$ur% l#ter pro2i(e( cl#ri1ic#tion t0#t 0#s l#r%el3 %one unnotice(4 5ritin% t0#t t0e respir#tion o1 c#ncer cells is s'#ll rel#ti2e to t0e consu'ption o1 %lucose4 $ut not s'#ll rel#ti2e to t0e respir#tion o1 nor'#l cells .?/& T0e con1usion '#3 0#2e $een pre2ente( 0#( "#r$ur% 1or'ul#te( 0is (e1inition o1 respir#tor3 i'p#ir'ent -B 3e#rs e#rlier&
"ille' 7& Koppenol #n( !#trici# L& Boun(s Institute o1 Inor%#nic C0e'istr34 Dep#rt'ent o1 C0e'istr3 #n( Applie( Biosciences4 ET74 "ol1%#n%8!#uli8Str#sse +B4 C78HB,- IJric04 S5itCerl#n(&

AIuD o .uien +enera el efecto ?arbur+ (fenoti*o de +luc/lisis aerobia$B

> !$ Alteraciones en la seJaliFaci/n de *K), myc, > > > > >
ras, a1t y :I@4I #$ (a*el de la *iru,ato 1inasa )$ :i*oGia del medio ambiente tumoral 6$ %utaciones del +en de ,on :i**el Lindau K$ %utaciones del +en de la succinato de2idro+enasa y<o +en de la fumarasa0 9$ Alteraci/n del e.uilibrio 7'A&4:84II (*otencial de membrana del *oro mitocondrial y 2eGosa1inasa4II$

All cancer cells but not nontransformed cells eG*ress a s*ecific s*lice ,ariant of *yru,ate 1inase, termed %#4(8, t2at is less acti,e, leadin+ to t2e build u* of *2os*2oenol*yru,ate0 ecent -or1 2as re,ealed t2at reduced acti,ity of %#4(8 *romotes a uni.ue +lycolytic *at2-ay in -2ic2 *2os*2oenol*yru,ate is con,erted to *yru,ate by a 2istidine4de*endent *2os*2orylation of *2os*2o+lycerate mutase, *romotin+ assimilation of +lycolytic *roducts into biomass

Biblio+rafia
>
#'ec< K4 Colet KM et #ll !!ARsA Inter1erence 5it0 "#r$ur% e11ect #n( clinic#l #ntic#ncer tri#ls& !!AR Rese#rc0 ol >B+> (oi +B&++::E>B+>E-B4L?B

>

#n(er 7ei(en MG4 C#ntle3 LC4M #n( T0o'pson CB Un(erst#n(in% t0e "#r$ur% E11ectA T0e Met#$olic Re<uire'ents o1 Cell !roli1er#tion Science ## %ay #HH"L ol& ->4 no& :,-B **0 !H#"4!H)) DOIA +B&++>?Escience&++?BHB,

> Bensin%er SK, C0risto19 7R

Ne- as*ects of t2e ?arbur+ effect in cancer cell biolo+y0 Semin &ell 'e, Biol0 #H!# MunN#)(6$L)K#49!

> N#N#1o2 A4 Alessi DR

Uncouplin% t0e "#r$ur% e11ect 1ro' C#ncer !NAS .>B+B/ +BLA+,+-:8+,+-?

:istory of :I@ researc2

> &lone t2e Eryt2ro*oietin +ene(!"OK$ > Eryt2ro*oietin induced by 2y*oGia(!"OP$ > 'isco,ery of 2y*oGic inducible nuclear factor > > > >
bindin+ to en2ancer of E(O +ene named as :I@4!(SemenFa GL !""#$ :I@4! acti,ity in cell not eG*ressin+ E(O durin+ 2y*oGia (!"")$ :I@4! is u*stream to 7EG@4Aetc0 7:L bind to :I@4! (!"""$ Gro-t2 factor and A8T u*stream :I@4!(!"""$

:I@4!
> A 2eterodimeric member of basic 2eliG4loo*42eliG > > >
(b:L:$ family, containin+ (AS domain &om*ose :I@4! Q and :I@4!R (ersistent eG*ression of :I@4! R, identical to aryl 2ydrocarbon rece*tor(A: $ nuclear translocator (A NT$ Bindin+ to 'NA se.uence K4(A<G$&GTG4)(: E$

Trends Cardiovasc med 1996;6:151-7

RAS

Raf

M !

R!

O,er,ie:I@4! si+nal *at2-ay

CCR 2003;9:4641-52 modified

La sor*resaL simbiosis metab/lica

> Los tumores se com*onen de dos ti*os
celularesL > A$ &Dlulas norm/Gicas .ue metaboliFan +lucosa y cido lactico > B$ &Dlulas 2i*/Gicas .ue *roducen cido lctico a *artir de +lucosa
El cido lctico *roducido *or las cDlulas 2i*/Gicas es incor*orado *or las cDlulas norm/Gicas y utiliFado *ara elaborar ener+Ea y otros *roductos
La enFima cla,e *ara este *roceso es %&T! (monocarboGilate trans*orter!$ Son,eauG et al0 T2e Mournal of &linical In,esti+ation #HHO 7ol !!O(!#$L )")H4)"6!

Symbiotic Metabolic Process