Improvement of treatment for prostate cancer and involvement of Plk1
Prostate cancer is the second most common cancer diagnosed for men in the U.S. Treatments for Castration resistant prostate cancer (CRPC) are limited. In this study, I found that co-targeting the p53 pathway and mitochondrial respiration led to inhibition of glycolysis and oxidative phosphorylation at the same time thus resulting in increased prostate cancer cell death. Although some treatments for prostate cancer inhibit prostate cancer progression, most patients eventually develop therapy resistance. Since activation of androgen receptor (AR) is responsible for progression of prostate cancer and drug resistance, I further tested additional ways to inhibit AR to overcome therapy resistance. I found that co-targeting HSP90 and its client proteins AR or Plk1 led to increased cancer cell death. I showed that co-targeting HSP90 and AR led to degradation of AR and inhibition of its activity and that Plk1 was involved as overexpression of Plk1 abolished combination effect. To further characterize the involvement of Plk1 in cancer progression, I identified IRS2 as a Plk1 substrate. Phosphorylation of IRS2 by Plk1 led to inhibition of the PI3K pathway and delayed mitotic exit, contributing to disorganized cell cycle progression and cancer progression. Our study dissected the novel roles of Plk1 in prostate cancer therapy and the PI3K pathway regulation, providing possible new ways to improve current prostate cancer treatment.
Liu, Purdue University.
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