Androgen-dependent mTORC1 Activation in Advanced Androgen Receptor (AR) Independent Prostate Cancer
Abstract
Prostate cancer is the leading cause of cancer death in American men, with >31,500 deaths estimated for 2019. Androgen deprivation therapy, the first-line treatment for advanced prostate cancer, reduces androgen levels to castration levels. Despite initial treatment success, castration-resistant prostate cancer (CRPC) eventually develops. An aggressive subset of CRPC is AR-independent, as tumor cells have lost AR expression. Novel genetic targets for cancer treatment include tumor suppressor genes such as phosphatase and tens in homolog (PTEN). PTEN is often mutated in early prostate cancer and CRPC, leading to constitutive activation of the PI3K/Akt/mTOR pathway.mTORC1 (mechanistic target of rapamycin) has arisen as a potential therapeutic candidate for advanced prostate cancer. The role of androgens in AR-negative prostate cancer in stimulating mTORC1 is unknown. I have demonstrated that androgens can stimulate mTORC1in a progesterone receptor membrane component 1 (PGRMC1)-dependent and PI3K, mTORC2 independent manner. Activation requires PGRMC1 as knockdown of PGRMC1, by siRNA or shRNA, or treatment with inhibitor AG-205, abrogated mTORC1 activation. I also show that PGRMC1 requires its cytochrome b5 binding domain as a truncated form of this protein when overexpressed (PGRMC1107-177) abrogates DHT-mediated phosphorylation. Moreover, I demonstrate a key tyrosine residue, Y113, is essential for PGRMC1 function and its ability to activate mTORC1. Overexpression of a dominant negative form of PGRMC1 (Y113F) fails to activate mTORC1. The converse is observed when a constitutively active form of PGRMC1 (Y113E) is overexpressed and can accomplish mTORC1 activation independent of DHT. These findings represent a novel and promising therapeutic target for a cohort of prostate cancer patients who have limited treatment options as all current second-line hormonal-targeted approaches, which revolve around targeting the AR, are ineffective.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2023
- Accession Number
- AD1211456
Entities
People
- Erik Hedrick
- Ritika Tiwari