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Li, Yuanzhe

University of British Columbia

Prostate Carcinoma (PCa) is the second most frequently diagnosed type of cancer and the fifth leading cause of mortality among males in the world. Androgen-deprivation therapy (ADT) is the first-line treatment option. Most PCa patients initially respond to androgen ablation, but eventually develop recurrent castration-resistant prostate cancer (CRPC). Current CRPC management combines chemotherapy like docetaxel with advanced ADT options like Enzalutamide and Abiraterone, extending survival but not curing, as chemoresistance eventually develops. Therefore, it is crucial to identify new molecular pathways that drive the chemoresistance, thereby discovering novel targets for developing innovative therapeutic to overcome resistance. Notch signaling has been previously illustrated to regulate cellular metabolism in cancer via different mechanisms. However, whether Notch signaling plays a regulatory role in prostate cancer remains unknown. In my dissertation, I investigated how Notch regulates metabolism in prostate cancer. I found that Notch1 positively regulates metabolic genes through PI3K-Akt-mTOR pathway. Notch signaling has been proven to participate in the development of chemoresistance prostate cancer. To explore the metabolic regulatory role of Notch in the development of chemoresistance, I used a docetaxel chemoresistance Du145 cell model and found that the Notch1 signaling pathway is highly activated in this chemoresistance cell line. Further explorations revealed that a Notch1 inhibitor can sufficiently block the PI3K-Akt-mTOR signaling and downstream metabolic genes as well as reduce glycolytic rate and triglyceride synthesis to the levels similarly to that produced by PI3K-Akt-mTOR inhibition. Most importantly, I found that Notch1 inhibition could block the tumor cell proliferation and that combination of Notch1 and mTOR inhibitors produced synergistic effects in suppressing the cancer cell proliferation. These data suggest that Notch1 signaling plays an essential role in chemoresistance development. In summary, this research demonstrates that through the mediation of the PI3K-Akt-mTOR signaling pathway, Notch1 plays a vital role in the metabolic rewiring during the development of chemoresistance in prostate cancers. The study provides strong evidence supporting a combination of Notch1 and mTOR inhibitors as a novel strategy overcome chemoresistance in late-stage prostate cancers.

Text

2024-04-04

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87685

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/