%0 Journal Article
%T Rictor-Dependent mTORC2 Signaling Drives Docetaxel Resistance in CRPC: Implications for Therapeutic Reversal
%A Andre Müller
%A Jana Roth
%J Pharmaceutical Sciences and Drug Design
%@ 3062-4428
%D 2024
%V 4
%N 1
%R 10.51847/Y707j7Vn3l
%P 91-102
%X The mammalian target of rapamycin (mTOR) is a major regulator of cell growth, proliferation, and the cell cycle. The primary component of mTORC2 is markedly upregulated in prostate cancer cells that have developed resistance to docetaxel. However, its specific molecular effects in prostate cells have not been fully defined.
A docetaxel-resistant prostate cancer cell line (PC-3/DTX) was established to examine the function of mTORC2 in drug resistance. Lentiviral vectors were used to silence Rictor expression, and cell viability was evaluated with the Cell Counting Kit-8 (CCK-8). Flow cytometry was conducted to assess cell cycle distribution, while changes in related signaling pathways were analyzed through immunohistochemistry (IHC) and Western blot assays.
PC-3/DTX cells with sh-RNA targeting Rictor showed the lowest IC50 for docetaxel. Reduced Rictor expression led to a greater proportion of cells arrested in the G0/G1 phase. When docetaxel treatment was repeated, IC50 values were lower in the AZD8055-treated group than in the Rapamycin group. Additionally, the AZD8055 group demonstrated a higher percentage of G0/G1-arrested PC-3/DTX cells compared with Rapamycin. IHC analysis of prostate cancer tissue from a CRPC patient showed elevated Rictor expression, while Raptor levels remained unchanged.This study examined the contribution of mTORC2 signaling to acquired docetaxel resistance in PC-3 cells to explore potential therapeutic strategies. mTORC2 activity is crucial for maintaining docetaxel resistance in PC-3 cells. The dual mTORC1/2 inhibitor AZD8055 more effectively disrupted mTORC2 kinase activity than the mTORC1-specific inhibitor Rapamycin, resulting in reduced resistance to docetaxel. Targeting this pathway may offer a promising approach to overcoming docetaxel resistance in patients with metastatic castration-resistant prostate cancer.
%U https://galaxypub.co/article/rictor-dependent-mtorc2-signaling-drives-docetaxel-resistance-in-crpc-implications-for-therapeutic-nsbbpg8hv3tt4tl