Targeting mTOR Complex 2 in Castration-Resistant Prostate Cancer with Acquired Docetaxel Resistance

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Mammalian Target of rapamycin (mTOR) regulates cell growth and proliferation.
• mTOR complex 2 (mTORC2) is highly expressed in docetaxel-resistant prostate cancer cells, but its role is unclear.
• Docetaxel resistance is a significant challenge in treating prostate cancer.

Purpose of the Study:

• To investigate the role of mTORC2 in acquired docetaxel resistance in prostate cancer cells.
• To identify potential therapeutic strategies to overcome docetaxel resistance by targeting mTORC2.
• To elucidate the molecular mechanisms underlying mTORC2's involvement in drug resistance.

Main Methods:

• Construction of a docetaxel-resistant human prostate cell line (PC-3/DTX).
• Knockdown of Rictor (a key component of mTORC2) using lentivirus.
• Assessment of cell viability (CCK-8), cell cycle (flow cytometry), and signaling pathways (IHC, Western blot).
• Treatment with mTOR inhibitors (AZD8055, Rapamycin) in combination with docetaxel.

Main Results:

• Decreased Rictor expression in PC-3/DTX cells led to G0/G1 cell cycle arrest and reduced viability.
• The mTORC1/2 inhibitor AZD8055 was more effective than the mTORC1 inhibitor Rapamycin in reducing docetaxel resistance.
• AZD8055 treatment resulted in greater G0/G1 cell cycle arrest compared to Rapamycin.
• Rictor was overexpressed in prostate cancer tissues from a castration-resistant prostate cancer (CRPC) patient.

Conclusions:

• mTORC2 signaling is essential for acquired docetaxel resistance in prostate cancer cells.
• Targeting mTORC2 with inhibitors like AZD8055 can reverse docetaxel resistance.
• Reversing docetaxel resistance by targeting mTORC2 presents a potential therapeutic option for mCRPC patients.