부산대학교 도서관

R3088 --> 700.3 --> Background: Chemotherapy remains the major treatment option for castration‐resistant prostate cancer (CRPC). Docetaxel (DTX)‐based chemotherapy provides significant survival benefit in patients with CRPC. However, the clinical utility of DTX is compromised when resistance is encountered. Therefore, a more thorough understanding of mechanisms underlying DTX resistance may potentially improve survival in patients with CRPC. The objective of this study is to investigate the role and mechanism of cholinergic receptor muscarinic 1 (CHRM1) activation upon chemotherapy resistance in PC and the efficacy of the CHRM1 antagonist dicyclomine (Dic) in treating DTX‐resistant PC. The hypothesis is that CHRM1 is essential for developing chemotherapy resistance in PC cells and driving survival and growth of DTX‐resistant PC cells. Methods: The CHRM1 expression levels and their association with DTX resistance were determined in PC clinical specimens and cultured cells. Human PC cells subjected to stable knockdown or overexpression of CHRM1 were evaluated for their response to DTX by cell proliferation, colony and tumorsphere formation, and TUNEL assays. Synergistic growth inhibition by combination treatment with DTX and Dic was assessed by cell viability and tumorgenicity assays. Results: CHRM1 expression was elevated under DTX treatment in CRPC 22Rv1 and DU145 cells, which was paralleled by higher CHRM1 expression in these cells after acquiring resistance to DTX (22Rv1DTXR and DU145DTXR). Immunohistochemical analyses revealed higher CHRM1 protein levels in longitudinally collected tumor tissues post‐ versus pre‐chemotherapy from a PC patient cohort. Enforced expression of CHRM1 increased DTX IC50 by up to 5‐fold, along with reduced cell apoptosis marker c‐PARP1 expression, in 22Rv1 and DU145 cells. Conversely, silencing of CHRM1 in 22Rv1DTXR cells decreased cell proliferation, invasion, and colony and tumorsphere formation. CHRM1 inactivation with Dic in combination with DTX resulted in more cell death of both DTX‐sensitive (22Rv1 and DU145) and ‐resistant (22Rv1DTXR, DU145DTXR and PC‐3DTXR) cells compared to either treatment alone. Further, Dic restored DTX sensitivity to suppress the growth of DTX‐resistant cells and xenograft tumors (22Rv1DTXR and PC‐3DTXR). Mechanistically, CHRM1 activation upregulated phosphoprotein levels of ERK, JNK and p38, which all are key players in the MAPK pathway and potential mediators driving chemoresistance in cancer cells, while Dic treatment reduced their phosphorylation levels in 22Rv1DTXR and DU145DTXR cells. Conclusion: Our results suggest that CHRM1 contributes to the development of DTX resistance in CRPC, which can be reversed by genetic or pharmacologic inactivation of CHRM1, providing new insights into developing a CHRM1‐targeted therapeutic strategy for overcoming DTX‐based chemotherapy resistance in CRPC. [ABSTRACT FROM AUTHOR]