Drug Design, Development and Therapy (Nov 2022)
Targeting mTOR Complex 2 in Castration-Resistant Prostate Cancer with Acquired Docetaxel Resistance
Abstract
Yujie Huang,1 You Zhai,1 Meijia Wu,1 Chengdong Chang,2 Jindan Luo,3 Dongsheng Hong,1 Qingwei Zhao,1 Yao Dai,4 Jian Liu1 1Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL, USACorrespondence: Jian Liu, Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China, Tel +86-571-87236560, Fax +86-571-87236531, Email [email protected] Yao Dai, Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL, USA, Tel +1-352-273-8237, Fax +1-352-273-8252, Email [email protected]: Mammalian Target of rapamycin (mTOR) plays a central role in regulating cell growth, proliferation, and cell cycle. The key component of mTORC2 is highly expressed in docetaxel-resistant prostate cells. However, the underlying molecular effects on prostate cells remain unclear.Methods: A docetaxel-resistant human prostate cell line (PC-3/DTX) was constructed to investigate the role of mTORC2 in docetaxel resistance. The lentivirus was transfected into cells to knock down the expression of Rictor, and cell viability was measured by Cell Counting Kit 8 (CCK-8). Flow cytometry was used to analyze the cell cycle, and the changes in related signal cascades were assessed by immunohistochemistry (IHC) staining and Western blot.Results: Docetaxel showed the lowest IC50 (50% inhibitory concentration) in PC-3/DTX cells with sh-RNA. Decreased Rictor expression resulted in a larger proportion of arrested cells in the G0/G1 phase in PC-3/DTX cells. The IC50 values of the AZD8055 group were lower than in the Rapamycin group when treated with docetaxel again. Furthermore, a larger proportion of PC-3/DTX cells were arrested in the G0/G1 phase in the AZD8055 group compared to the Rapamycin group. The IHC results of the prostate cancer tissues from a CRPC patient revealed the over expression of Rictor only, while Raptor expression was unaffected.Conclusion: We investigated the role of mTORC2 signaling on the acquired docetaxel -resistant PC-3 cells to identify potential methods for clinical treatment. MTORC2 expression is essential for docetaxel drug resistance of PC-3 cells. The mTORC1/2 inhibitor AZD8055 caused more significant disruption of mTORC2 kinase activity than the mTORC1 inhibitor Rapamycin, which lead to decreased docetaxel-mediated resistance. Therefore, reversing docetaxel resistance, may become a therapeutic option in the treatment of mCRPC patients.Keywords: prostate cancer cell, docetaxel, drug resistance, mTORC2, reverse
