Cancer and Apoptosis combined

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Cancer and Apoptosis combined An historical
introduction Mathieu Noteborn LIC, Leiden
University, NL LC Workshop - 29 October 2007
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Cancer and Apoptosis combined An historical
Introduction Apoptosis versus cancer Viruses
inducing Cancer lessons to be learned Proteins
killing tumor cells Apoptin E4orf4 HAMLET MDA7
NS1 TRAIL A brief preview to our workshop
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Apoptosis and life belong together
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Apoptosis is a genetically regulated network of
pathways
Imbalances in apoptosis pathways underlie many
different diseases
Factors can positively or negatively interfere
with apoptosis machinery
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Interference in apoptosis machinery Induction
Inhibition
West Nile virus induces apoptosis in brain cells
resulting in meningitis/encephalitis
Inhibition of apoptosis results in tumor cell
formation
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Interference at various steps in the apoptotic
machinery results in tumor formation
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Living with p53, dying of p53
Cellular background
Cellular background
Mutated p53/partners might result in genetic
instability/cancer
Aylon Oren, 2007
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Up-regulation of anti-apoptotic proteins results
in tumor formation
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Bcl-2/BclXl form dimers via their BH3
domains with each other or with pro-apoptotic
family members
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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
EpiGalleCatechin Gallate EGCG Reed, 2006
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Expression of Livin causes chemo-resistance of
tumor cells
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Down-regulation of Livin sensitizes tumor cells
to chemotherapeutic drugs
Liu et al., 2007
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Aberrancies in Bcl-2, p53 Fas tumor beats
our defense mechanism
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Apoptosis versus Cancer Summary Defects in
apoptosis pathways Contribute to
cancer Permitting aberrant cell
behavior Desensitizing tumor cells
to Immune-mediated attack Chemotherapy Canc
er development and anti-cancer therapy
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Cancer and Apoptosis combined An historical
Introduction Apoptosis versus cancer Viruses
inducing Cancer lessons to be learned Proteins
killing tumor cells Apoptin E4orf4 HAMLET MDA7
NS1 TRAIL A brief preview to our workshop
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DNA tumor viruses Papilloma virus Adenovirus He
rpesvirus Epstein Barr virus Hepatitis B
virus Polyoma virus SV40 RNA tumor
viruses Retroviruses
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SV40 transforms cells SV40 LT
interacts with tumor suppressor p53
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DNA-tumor viruses express proteins
interfering with cellular factors resulting in
cellular transformation
OShea, 2004
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SV40 LT and st have transforming activities
LT interacts with e.g. p53, Rb st interacts
with PP2A

Pipas
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PP2A-dependent pathways targeted by SV40
st contributes to cell transformation
Arroyo
Sontag Sontag, 2006
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. and most likely much more gene products
are affected by st synthesis Affymetrix
studies SV40 st affects e.g. expression of
factors within the Wnt, Hedgehog Notch
pathways Ali-Seyed et al., 2006
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SV40 st affects Apoptosis Pathways Down-regulation
expression of pro-apoptotic factors Up-regulation
expression of anti-apoptotic factors
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DNA tumor viruses apoptosis SV40 transforming
LT and st Inhibition of pro-apoptotic processes
(p53/caspase) Stimulation of anti-apoptotic
processes (survivin) Adenovirus
proteins Inhibition of pro-apoptotic
processes Stimulation of anti-apoptotic
processes ?
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Transforming adenovirus inhibits and induces
apoptosis
White, 2006
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SV40 LT/st inhibits apoptosis Adenovirus E1B
proteins inhibit apoptosis Adenovirus E1A induces
apoptosis Why does transforming adenovirus
harbor E1A protein? Apoptosis is an essential
step in (Ad) transformation?
Next Oncolytic viruses require transformation
events to induce cell death/apoptosis
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Oncolytic Viruses
E.g. Parvovirus H1, Newcastle Disease Virus,
(engineered) Adenovirus

Vähä-Koskela et al., 2007
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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
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Using viruses in conjunction with other forms of
treatment
Nuesch/Rommelaere
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Viruses inducing cancer lessons to be
learned Summary Viruses transform cells by
inhibiting apoptosis SV40 Viruses transform
cells by inhibiting inducing apoptosis Adenov
irus others? Oncolytic viruses use
transforming events to kill cells Parvovirus H1
(NS1 protein) Newcastle disease virus
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Cancer and Apoptosis combined An historical
Introduction Apoptosis versus cancer Viruses
inducing Cancer lessons to be learned Proteins
killing tumor cells Apoptin E4orf4 HAMLET MDA7
NS1 TRAIL A brief preview to our workshop
31
Transforming events are needed for proteins
inducing tumor-specific apoptosis Use of a
paradox?
DNA damage
Pathway interference affecting cell transformation
Apoptin, E4orf4, HAMLET, NS1, MDA7, TRAIL All
seem to sense tumor-specific processes
Abrahams, unpublished
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Transformation events activate apoptin
N localization
LT/st
SV40 LT/st are transforming proteins
Peng
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E4orf4 affects directly tumor-related PP2A
Lavoie
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Tumor factors encountered by HAMLET - MDA7
TRAIL
TRAIL
MDA7
Svanborg Ramesh Walczak Borst
HAMLET
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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 Editors Backe
ndorf Borst - Noteborn Tavassoli
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Organizers C Backendorf, J Borst M Noteborn M
Tavassoli Advisory Board members J Brouwer, M
Green, F Farzaneh AJ van der Eb WISH YOU A
VERY FRUITFUL LC-WORKSHOP
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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