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Cancer and Apoptosis combined An historical introduction Mathieu Noteborn

Cancer and Apoptosis combined An historical introduction Mathieu Noteborn LIC, Leiden University, NL LC Workshop - 29 October 2007. Cancer and Apoptosis combined An historical Introduction Apoptosis versus cancer Viruses inducing Cancer: lessons to be learned Proteins killing tumor cells

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Cancer and Apoptosis combined An historical introduction Mathieu Noteborn

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  1. Cancer and Apoptosis combined An historical introduction Mathieu Noteborn LIC, Leiden University, NL LC Workshop - 29 October 2007

  2. 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

  3. Apoptosis and life belong together

  4. 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

  5. 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

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

  7. “Living with p53, dying of p53” Cellular background Cellular background Mutated p53/partners might result in genetic instability/cancer Aylon & Oren, 2007

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

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

  10. 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

  11. Expression of Livin causes chemo-resistance of tumor cells

  12. Down-regulation of Livin sensitizes tumor cells to chemotherapeutic drugs Liu et al., 2007

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

  14. Apoptosis versus Cancer Summary 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

  15. 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

  16. DNA tumor viruses Papilloma virus Adenovirus Herpesvirus Epstein Barr virus Hepatitis B virus Polyoma virus SV40 RNA tumor viruses Retroviruses

  17. SV40 transforms cells SV40 LT interacts with tumor suppressor p53

  18. DNA-tumor viruses express proteins interfering with cellular factors resulting in cellular transformation O’Shea, 2004

  19. SV40 LT and st have transforming activities LT interacts with e.g. p53, Rb st interacts with PP2A Pipas

  20. PP2A-dependent pathways targeted by SV40 st contributes to cell transformation Arroyo Sontag & Sontag, 2006

  21. …. 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

  22. SV40 st affects Apoptosis Pathways Down-regulation expression of pro-apoptotic factors Up-regulation expression of anti-apoptotic factors

  23. 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 ?

  24. Transforming adenovirus inhibits and induces apoptosis White, 2006

  25. 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

  26. Oncolytic Viruses E.g. Parvovirus H1, Newcastle Disease Virus, (engineered) Adenovirus Vähä-Koskela et al., 2007

  27. 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

  28. Using viruses in conjunction with other forms of treatment Nuesch/Rommelaere

  29. Viruses inducing cancer: lessons to be learned Summary Viruses transform cells by inhibiting apoptosis SV40 Viruses transform cells by inhibiting & inducing apoptosis Adenovirus + others? Oncolytic viruses “use” transforming events to kill cells Parvovirus H1 (NS1 protein) Newcastle disease virus

  30. 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. Arrest Apoptosis Apoptosis Survival 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

  32. Normal cells Apoptosis Apoptin + LT Phosphorylation Apoptin a-108P Transformation events activate apoptin N localization + LT/st SV40 LT/st are transforming proteins Peng

  33. PP2A E4orf4 affects directly tumor-related PP2A Lavoie

  34. Tumor factors encountered by HAMLET - MDA7 – TRAIL TRAIL MDA7 Svanborg Ramesh Walczak & Borst HAMLET

  35. 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 Backendorf – Borst - Noteborn – Tavassoli

  36. 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

  37. 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

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