Survival and apoptosis A dysregulated balance in ... · Survival and apoptosis A dysregulated...
Transcript of Survival and apoptosis A dysregulated balance in ... · Survival and apoptosis A dysregulated...
Survival and apoptosisA dysregulated balance in colorectal cancer?
Isabel FabregatInstitut d’Invetigació Biomèdica de Bellvitge
L’Hospitalet, Barcelona, [email protected]
Proliferation Cell death
Homeostasis
PROLIFE -
RACIÓN
MUERTE
CELULARPROLIFERATION
CELLDEATH
Proliferation Cell death
Tumor
PROLIFE-RACIÓN
MUERTECELULAR
-
CELLDEATH
PROLIFERATION
Signalling pathways involved in physiological apoptosis
CHARACTERISTICSCHARACTERISTICS OFOF APOPTOSISAPOPTOSIS
Selective proteolysis: CASPASES
- 116- 85
PARP
PHAGOCYTOSIS
- Phosphatidylserine exposition
Anexina VFITC
Chromatin condensation and nuclear fragmentation
DNA (IP)C
ell n
umbe
r
<2n
Fragmentation of the genomicDNA
180 bp
End
onuc
leas
e
Appearance of blebs in the cell membrane
No inflammation
Apoptotic bodies
CASPASESCASPASES: : CYSTEINCYSTEIN ASPARTATEASPARTATE PROTEASESPROTEASES
ACTIVE CASPASE (TETRAMER)
XXXAsp
PROTEOLYSIS (1000 SUBSTRATES)
INACTIVE PRECURSOR
CATALYTIC CENTERQACR(or Q/G)G
Asp Asp
Caspase-3, Caspase-7
(Initiator)
Apaf-1
AIF
Caspase-8
Bid
t-Bid
Bax
X-IA
P
SMAC/DIABLO
Cytochrome C
INTR
INSI
CPA
THW
AYpr
oCas
pase
-8Bcl-2Mcl-1
APOPTOSIS
EXTR
INSI
CPA
THW
AY
Caspase-9
Apoptosome
DISC
FasTNFRTRAILR
Cell death receptors
Ligands
Cellular stress
EndoG
(Initiator)
(Executioner)
BCL-2 FAMILY
Anti-apoptotic
Proapoptotic
Multidomain
BH3-only
Bcl-2 Bcl-xLMcl-1 Bcl-wBfl-1/A1 Diva/BooBrag-1
Bax BakBok/Mtd Bcl-XSBcl-GL
Bad Bid Bnip1 Mil1/Bcl-ramboBim Puma Bmf Nix/Bnip3LBik/Blk Noxa/apr Bfk Nip1/Bnip1Hrk/DP5 Bnip3 Bpr Bnip3h
BH4BH3BH1BH2TM
Cell damage sensors
Regulation ofmultidomain pro- and
antiapoptoticmembers
Caspase-3, Caspase-7
(Initiator)
Apaf-1
AIF
Caspase-8
Bid
t-Bid
Bax
X-IA
P
SMAC/DIABLO
Cytochrome C
INTR
INSI
CPA
THW
AYpr
oCas
pase
-8Bcl-2Mcl-1
APOPTOSIS
EXTR
INSI
CPA
THW
AY
Caspase-9
Apoptosome
DISC
FasTNFRTRAIL
Cell death receptors
Ligands
Cellular stress
EndoG
(Initiator)
(Executioner)
SIGNALLING PATHWAYS INVOLVED IN EPITHELIAL CELL SURVIVAL
Extracellular
Cytoplasm
Nucleus
RTK
GFs
EGFRs
c-MET
PI3K
AKT/PKB
mTOR
P70 S6K
Translation of cell cycleregulatory proteins
Stat
Ras
Raf
MEK1/2
ERK
ERK
P27kip1, c-Myc, c-Fos, cyclinB.
PTEN
BadForkhead
ProGFs
PROLIFERATION
SURVIVAL
EGF/HB-EGF/TGFα/amphiregulin
HGF
TACE / ADAMs
Two major pathways playing essential roles in epithelial cell survival
bcl-2, mcl-1
CREB
P90 RSK
Fas , other pro-apoptotic factors
SOME CYTOKINES PLAY DUAL ROLES IN CONTROLLING CELL DEATH
Extracellular
Cytoplasm
Nucleus
RTK
GFsEGF/HB-EGF/TGFα/amphiregulin
HGF
EGFRs
c-MET
PI3K
AKT/PKB
mTOR
P70 S6K
Translation of cell cycleregulatory proteins
Stat
Ras
Raf
MEK1/2
ERK
ERK
P27kip1, c-Myc, c-Fos, cyclinB.
TNFR1
IKKKs
IKK
NFκB
P-IκB
NFκB
c-IAPs, XIAP, c-FLIP, Survivin, TRAF2, Bcl-XL, Mcl-1, MnSOD, FHC
TNFα
TRADD-TRAF2-RIP
ASK1
MKK4,7
JNK
c-Jun
PTEN
CREB
P90 RSK
BadForkhead
TRADD- TRAF2-RIP, FADD
TRAIL-R1
TRAIL FAS L
FAS
Caspase-8,-10c-FLIP
Caspase-3,-6,-7
APOPTOSIS
Bid
Cyt c
Bcl-2 BclXL
Casp-9Apaf-1
Apoptosome
TACE / ADAMs
ProGFs
BadBax
Smac/Diablo
IAPsAKT
PROLIFERATIONSURVIVAL
APOPTOSIS
SURVIVALbcl-2, mcl-1
ROSGlutathione
ΔΨm
cit-C
APOPTOSIS
Caspase-9 Caspases 3 and 8
NADPHoxCHXAntioxidants
PI-3K
SURVIVAL
TGF-β TGF-αHB-EGF
TACE
Fetal rat hepatocytesFaO rat hepatoma cells
Epithelial-mesenchymal transitionprocesses
EGFR
Murillo et al. Oncogene 2005Caja et al. Cell. Signal. 2007
Ser-threo Kinase
Epithelial to Mesenchymal transitions:In the crossroads to apoptosis
resistance and cell invasion
RT - 3 5 8 16 24 36 48
snail
E-cadherin
+ TGFβ (h)
alb
TGFβ also changes the expression of some genes involved in epithelial to mesenchymal transitions
Caja et al. Cell Signal 2007
1 day 3 daysControl
E-CAD
DAPI
Control TGFβ
ControlTGFβ
FaO
Phalloidin
The EMT confer resistance to apoptosis. Snail activates survival pathways
Vega et al.Genes & Dev 2004
Increase in migration, apoptosis resistance…
METASTATIC POTENTIAL
Dysregulation of the apoptosis/survival pathway in
colorectal cancer
APOPTOSIS
PTEN
FAS
Bax, Bak
p53
SURVIVAL
Survivin
Bcl-2
HGF
β-catenin
EGFR ligands
PI-3K/AKTApaf1TβRII
P53, a guardian of the genome and a policeman of oncogenes
Puma, Noxa
Fas
Survival signals
Inflammation, colorectal cancer and NF-κB
Watson AJM, Crit Rev Onc Hematol, 2006
Inflammation, colorectal cancer and COX-2
Wand D and DuBois RN. Gut 2006
APOPTOSIS
PTEN
FAS
Bax, Bak
p53
SURVIVAL
SurvivinBcl-2
HGF
β-catenin
EGFR ligands
PI-3K/AKTApaf1TβRII
NF-κB
COX-2
APOPTOSIS
PTEN
FAS
Bax, Bak
p53
SURVIVALHGF
Survivin
β-catenin
Bcl-2
EGFR ligands
PI-3K/AKT
Apaf1
The balance between survival and apoptosis is dysregulated in colorectal cancer
NF-κB
COX-2
……Although multiple variables undoubtedly contribute to clinical outcome for patients diagnosed with early-stage colorectal cancer, these preliminary findings indicate that cIAP2, Apaf1, TUCAN, and Bcl-2 deserve further evaluation as potential prognostic markers. If confirmed in prospective studies, such prognostic biomarkers may help to guide treatment decisions for colorectal cancer patients, particularly regarding use of adjuvant chemotherapy.
Clin Cancer Res 2005;11(15) August 1, 2005
BiologBiologíía Molecular II. Facultada Molecular II. Facultadde Farmacia, de Farmacia, UCMUCM
Departamento de BioquDepartamento de Bioquíímica ymica yBiologBiologíía Molecular II. Facultada Molecular II. Facultad
de Farmacia, de Farmacia, UCMUCM
Irene CarmonaGaelle del CastilloAránzazu Sánchez
Margarita FernándezCésar Roncero
Laia CajaMiguel Murillo Conrad Ortiz
Esther BertranPatricia SanchoIsabel Fabregat
IDIBELL-Institut de Investigació Biomèdica de
BellvitgeL´Hospitalet, Barcelona
Instituto de Neurociencias, CSIC-Univ. Miguel Hernández, Alicante
Sonia Vega Ángela M. Nieto
CNIC , Instituto Salud Carlos III, Madrid
Alberto Álvarez-Barrientos
University of Vienna, Austria
Wolfgang Mikulits lab
Natalia Lazarevich(University of Moscow, Russia)