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Permanent link (DOI): https://doi.org/10.7939/R3CQ5D

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

Descriptions

Other title
Subject/Keyword
apoptosis
cancer therapy
melanoma
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Keuling, Angela
Supervisor and department
Andrew, Susan (Medical Genetics)
Tron, Victor (Pathology and Molecular Medicine, Queen's University
Examining committee member and department
Bleoo, Stacey (Medical Genetics)
Korneluk Robert (Apoptosis Research Centre, University of Ottawa)
Goping, Ing Swie (Biochemistry)
Underhill, Alan (Medical Genetics and Oncology)
Department
Medical Sciences - Medical Genetics
Specialization

Date accepted
2010-03-12T15:30:49Z
Graduation date
2010-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R3CQ5D
Rights
License granted by Angela Keuling (akeuling@ualberta.ca) on 2010-02-26T19:11:25Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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File author: Angela Keuling
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