Apoptosis evasion in cancer cells

How cancer cells evade apoptosis

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Hallmarksof

Cancer

Self-

suffic

iency

in

prolife

ration

sign

als

Insensitivity to proliferation

inhibiting signals

Evading apoptosis

Tissue invasion &

metastasis

Lim

itles

s re

plic

ativ

e po

tent

ial

Susta

ined

angio

gene

sis

Metabolic reprogramming

Escape from

immune controlATP

STOPGROWTH FACTOR RECEPTOR

PROTEIN KINASES

DEATH-CAUSING PROTEASES

DEATH-INDUCING LIGANDS

GROWTH FACTOR

APOPTOSIS-INDUCING PROTEINS

TRANSCRIPTION FACTORDEATH RECEPTORS

ACTIVATION

INDIRECT ACTIVATION

DOWNSTREAM EFFECT

INHIBITION

TRANSLOCATION

LEGEND4 p53 Mutations

The pro-apoptotic regulator, p53, is a key tumor suppressor and is mutated in many cancers.

3 Upregulated Apoptosis Inhibiting Pathways

Cancer cells can overcome apoptosis via the upregulation of apoptosis inhibiting pathways, such as the PI 3 kinase (PI 3K)-Akt/PKB survival pathway and BCL2 overexpression. Loss of the tumor suppressor gene PTEN also inhibits apoptosis.

2 Elevated Oncogene Signaling

Persistent, and/or elevated signaling from oncogenes can drive cell proliferation that can shift the balance over a cell’s apoptotic program.

Cancer cells can escape apoptotic programming by upregulating the expression of non-signaling decoy receptors for the FAS ligand, which may prevent activation of the FAS receptor and downstream apoptosis.

1 Decoy Receptor Expression

TNFα

FasL

Fas

TNFR1

GrowthFactor

Growth FactorReceptor

Withdrawal ofGrowth Factors

Depolarization

OncogenicSignal

Apo2/Apo3

Apo2L/Apo3L

ELEVATED ONCOGENE SIGNALING2

DECOY RECEPTOR EXPRESSION1

p53 MUTATIONS4

MDM2

UPREGULATED APOPTOSIS INHIBITING PATHWAYS

3

p53

FADD

FADD FADD TRADD

TRAF2

Mitochondria

RIP

PKC

BID

Iκbs

IKKsFLIP

CIAP1

NF-κB

NF-κB

BAD

PBRVDAC

CypD

BAKBAX

IBID

BCLXL

MMP

ANT BIM

PUMANoxa

AIFEndoGApoptosis

Apoptosis

Apoptosis

DNAFragmentation

BAX, BAK, BID,Ras, Noxa, PUMA,APAF1, Survivin

FLIP, CIAP2, BFL1, BCL2

POD

Apoptosis

DNA Fragmentation

p53AIP1

BCL2

p90RSK

RAS

PIP3

PTEN

Procaspase8

Caspase8

Caspase3

Caspase7

ICAD

CAD

Caspase9

APAF1

CytoC

PML PAR4

DaxxZIPK

PARP CAD ATM

Chk2

EndoG

SMAC

Arts

HTRA2

Procaspase8Procaspase8

p53

AIF

p14(ARF)

FasL

Akt1

PI 3-K

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