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Characterization of the response of melanoma cell lines to inhibition of anti-apoptotic Bcl-2 proteins

  • Author / Creator
    Keuling, Angela
  • Malignant melanoma is resistant to almost all conventional forms of chemotherapy. Recent evidence suggests that anti-apoptotic proteins of the Bcl-2 family are overexpressed in melanoma and may contribute to melanoma’s striking resistance to apoptosis. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xl and Bcl-w, has demonstrated efficacy in several forms of cancer. However, overexpression of Mcl-1, a frequent observance in melanoma, is known to confer ABT-737 resistance. My results demonstrate that the combination of ABT-737 and RNA silencing of Mcl-1 induces significant cell death in six different melanoma cell lines, representing a potential new therapeutic strategy. I show that the apoptotic response to the combination treatment involves both the intrinsic pathway and a death receptor-independent role for extrinsic pathway proteins. The combination treatment also induces a number of gene expression changes as assessed by cDNA microarray and follow-up analyses. Based on the results of the array, I investigated the effects of inhibition of MAPK proteins combined with ABT-737 and/or Mcl-1 knockdown. I found that the combination of a p38 MAPK inhibitor and ABT-737 strongly and synergistically induces apoptosis in melanoma cell lines, thus suggesting a second novel treatment combination with potential for melanoma therapy. Finally, I provide novel evidence that Bcl-2 family member PUMA is cleaved in a caspase-dependent fashion during apoptosis and may play a role in treatment response. Currently, there are no effective treatments for metastatic melanoma. My findings describe two potential combination therapies for melanoma as well as provide novel evidence as to the mechanisms involved in treatment response.

  • Subjects / Keywords
  • Graduation date
    2010-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3CQ5D
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Medical Sciences - Medical Genetics
  • Supervisor / co-supervisor and their department(s)
    • Tron, Victor (Pathology and Molecular Medicine, Queen's University
    • Andrew, Susan (Medical Genetics)
  • Examining committee members and their departments
    • Bleoo, Stacey (Medical Genetics)
    • Goping, Ing Swie (Biochemistry)
    • Korneluk Robert (Apoptosis Research Centre, University of Ottawa)
    • Underhill, Alan (Medical Genetics and Oncology)