Cancer and Apoptosis combined

An historical introduction

Mathieu Noteborn

LIC, Leiden University, NL

LC Workshop - 29 October 2007

Cancer and Apoptosis combinedAn historical Introduction

Apoptosis versus cancer

Viruses inducing Cancer: lessons to be learned

Proteins killing tumor cellsApoptin E4orf4 HAMLET MDA7 NS1 TRAIL

A brief preview to our workshop

Apoptosis and lifebelong together

Apoptosis is a genetically regulatednetwork of pathways

Factors can “positively or negatively” interfere with apoptosis machinery

Imbalances in apoptosis pathwaysunderlie many different diseases

West Nile virus induces apoptosis in brain cells resulting in meningitis/encephalitis

Inhibition of apoptosis resultsin tumor cell formation

Interference in apoptosis machinery

Induction Inhibition

Interference at various steps in the apoptotic machinery results in tumor formation

“Living with p53, dying of p53”

Aylon & Oren, 2007

Mutated p53/partners might result in genetic instability/cancer

Cellularbackground

Cellularbackground

Up-regulation of anti-apoptotic proteins results in tumor formation

Bcl-2/BclXl form dimers via their BH3 domainswith each other or with pro-apoptotic family members

EpiGalleCatechin Gallate; EGCG

Reed, 2006

Prevention of formation of anti-apoptotic Bcl-2 homo- or hetero-dimers results in killing of tumor cells

anti-apoptotic proteins as Bcl-2 are potential drug targets

Expression of Livin causes chemo-resistance of tumor cells

Liu et al., 2007

Down-regulation of Livin sensitizes tumor cells to chemotherapeutic drugs

Aberrancies in Bcl-2, p53 & Fas: tumor “beats” our defense mechanism

Apoptosis versus CancerSummary

Defects in apoptosis pathways

Contribute to cancer

Permitting aberrant cell behavior

Desensitizing tumor cells to:Immune-mediated attack Chemotherapy

Cancer development and anti-cancer therapy

Cancer and Apoptosis combinedAn historical Introduction

Apoptosis versus cancer

Viruses inducing Cancer: lessons to be learned

Proteins killing tumor cellsApoptin E4orf4 HAMLET MDA7 NS1 TRAIL

A brief preview to our workshop

DNA tumor virusesPapilloma virusAdenovirusHerpesvirusEpstein Barr virusHepatitis B virusPolyoma virus

SV40

RNA tumor virusesRetroviruses

SV40 transforms cells

SV40 LT interacts with tumor suppressor p53

DNA-tumor viruses express proteins interferingwith cellular factors resulting in cellular transformation

O’Shea, 2004

SV40 LT and st have transforming activities

LT interactswith e.g. p53, Rb

st interacts withPP2A

Pipas

PP2A-dependent pathways targeted by SV40 stcontributes to cell transformation

Sontag & Sontag, 2006Arroyo

…. and most likely muchmore gene products areaffected by st synthesis

Affymetrix studies

SV40 st affects e.g.expression of factorswithin the Wnt, Hedgehog& Notch pathways

Ali-Seyed et al., 2006

SV40 st affects Apoptosis PathwaysDown-regulation expression of pro-apoptotic factorsUp-regulation expression of anti-apoptotic factors

DNA tumor viruses & apoptosis

SV40 transforming LT and st Inhibition of pro-apoptotic processes (p53/caspase)Stimulation of anti-apoptotic processes (survivin)

Adenovirus proteinsInhibition of pro-apoptotic processesStimulation of anti-apoptotic processes?

White, 2006

Transforming adenovirus inhibits and induces apoptosis

SV40 LT/st inhibits apoptosis

Adenovirus E1B proteins inhibit apoptosisAdenovirus E1A induces apoptosis

Why does transforming adenovirus harbor E1A protein?Apoptosis is an essential step in (Ad) transformation?

NextOncolytic viruses require transformation events to induce cell death/apoptosis

Oncolytic Viruses

E.g. Parvovirus H1, Newcastle Disease Virus, (engineered) Adenovirus

Vähä-Koskela et al., 2007

Molecular basis for selective permissiveness of cancer cells to oncolytic viruses

- Chromosomal instability

- Apoptosis resistance

- Higher levels of virus receptors (e.g. ICAM-1)

- Impaired anti-viral response (lack of critical IFN response)

- Adenovirus lacking E1B grows only in p53-minus cells

Using viruses in conjunction with other forms of treatment

Nuesch/Rommelaere

Viruses inducing cancer: lessons to be learnedSummary

Viruses transform cells by inhibiting apoptosisSV40

Viruses transform cells by inhibiting & inducing apoptosis

Adenovirus + others?

Oncolytic viruses “use” transforming events to kill cellsParvovirus H1 (NS1 protein)Newcastle disease virus

Cancer and Apoptosis combinedAn historical Introduction

Apoptosis versus cancer

Viruses inducing Cancer: lessons to be learned

Proteins killing tumor cellsApoptin E4orf4 HAMLET MDA7 NS1 TRAIL

A brief preview to our workshop

Transforming events are needed for proteins inducing tumor-specific apoptosis: Use of a

paradox?

DNA damage

Apoptosis

Arrest

Apoptosis

Survival

Pathway interference affecting cell transformation

Apoptin, E4orf4, HAMLET, NS1, MDA7, TRAIL

All seem to sense tumor-specific processes

Abrahams, unpublished

Transformation events activate apoptin

ApoptosisNormal cells

+ LT/st

N localization

Apoptin + LTApoptin

a-108P

Phosphorylation

PengSV40 LT/st are transforming proteins

E4orf4 affects directly tumor-related PP2A

PP2A

Lavoie

Tumor factors encountered by HAMLET - MDA7 – TRAIL

TRAILMDA7

HAMLET

SvanborgRameshWalczak & Borst

All Participants are invited to send in their contribution to the book

“Proteins Killing Tumour Cells”

Within the Research SignPost Series on

Cell Death and Disease

EditorsBackendorf – Borst - Noteborn – Tavassoli

Organizers C Backendorf, J Borst

M Noteborn & M Tavassoli

Advisory Board membersJ Brouwer, M Green,

F Farzaneh & AJ van der Eb

WISH YOU A VERYFRUITFUL

LC-WORKSHOP

References

Ali-Seyed et al., 2006, BMC Cancer 6, 54

Aylon & Oren, 2007, Cell 130, 597

Kooistra et al., Nov. 2007, MRMC, in press

Liu et al., 2007, Cancer Letters 250, 168

Reed, 2006, Nature Clinical Practice 3, 388

Sontag & Sontag, 2006, Cell. Mol. Life Sciences 63, 2979

Vähä-Koskela et al., 2007, Cancer Letters, 254, 178

White, 2006, Cell Death & Differentiation 13, 1371