Grants and Contracts Details
Description
The proteasome is a large protein complex responsible for the degradation of >80% of cellular
proteins. It is the major player of the highly-regulated ubiquitin-proteasome system, which is
important in controlling a myriad of cellular processes. It has been previously demonstrated that
fast-dividing cancer cells are more reliant on proteasome activity for growth and survival. Based
on this, the proteasome was exploited as a potential anti-cancer target. This lead to the
development of proteasome inhibitor agents bortezomib and carfilzomib that now comprise a
class of chemotherapy that is integral to the treatment of multiple myeloma. However, one of the
major challenges in the continued use of proteasome inhibitor therapy is drug resistance. Thus,
in order to expand the therapeutic utility of proteasome inhibitor agents, it is important to
understand the mechanisms underlying the inherent differences in sensitivity as well as the
development of acquired resistance.
Several mechanisms of PI resistance have been proposed previously, however these
mechanisms have not been identified in the clinic, nor do they account for all proteasome
inhibitor resistance observed. In this regard, our goal is to identify additional mechanisms that
may be responsible for the development of proteasome inhibitor resistance. In the current
proposal, we hypothesize that accelerated proteasome turnover via autophagy-mediated
processes may contribute to the development of proteasome inhibitor resistance in cancer cells.
This is based on our preliminary findings indicating that carfilzomib-resistant cells have rapid
recovery of proteasome activity following initial inhibition at a rate that is faster than the
expected proteasome turnover rate. We will validate our hypothesis by comparing the rates of
proteasome turnover in pancreatic cancer cell line models with different sensitivities to
proteasome inhibition. We will also investigate the involvement of the autophagy-lysosome
pathway in the degradation of proteasomes, as well as the role of autophagy in the development
of proteasome inhibitor resistance. These studies may provide additional insight into the
molecular changes responsible for the development of resistance. Such information may be
important for the design of next-generation proteasome inhibitors, or alternative combination
therapies to overcome resistance.
Status | Finished |
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Effective start/end date | 9/1/15 → 8/31/16 |
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