Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cell Commun Signal. 2024 Oct 24;22(1):517. doi: 10.1186/s12964-024-01897-z.
Enzalutamide (Enz) resistance is a poor prognostic factor for patients with castration-resistant prostate cancer (CRPC), which often involves aberrant expression of the androgen receptor (AR). Myosin VI (MYO6), one member of the myosin family, plays an important role in regulating cell survival and is highly expressed in prostate cancer (PCa). However, whether MYO6 is involved in Enz resistance in CRPC and its mechanism remain unclear.
Multiple open-access databases were utilized to examine the relationship between MYO6 expression and PCa progression, and to screen differentially expressed genes (DEGs) and potential signaling pathways associated with the MYO6-regulated Enz resistance. Both in vitro and in vivo tumorigenesis assays were employed to examine the impact of MYO6 on the growth and Enz resistance of PCa cells. Human PCa tissues and related clinical biochemical data were utilized to identify the role of MYO6 in promoting PCa progression and Enz resistance. The molecular mechanisms underlying the regulation of gene expression, PCa progression, and Enz resistance in CRPC by MYO6 were investigated.
MYO6 expression increases in patients with PCa and is positively correlated with AR expression in PCa cell lines and tissues. Overexpression of AR increases MYO6 expression to promote PCa cell proliferation, migration and invasion, and to inhibit PCa cell apoptosis; whereas knockdown of MYO6 expression reverses these outcomes and enhances Enz function in suppressing the proliferation of the Enz- sensitive and resistant PCa cells both in vitro and in vivo. Mechanistically, AR binds directly to the promoter region (residues - 503 to - 283 base pairs) of MYO6 gene and promotes its transcription. Furthermore, MYO6 activates focal adhesion kinase (FAK) phosphorylation at tyrosine-397 through integrin beta 8 (ITGB8) modulation to promote PCa progression and Enz resistance. Notably, inhibition of FAK activity by Y15, an inhibitor of FAK, can resensitize CRPC cells to Enz treatment in cell lines and mouse xenograft models.
MYO6 has pro-tumor and Enz-resistant effects in CRPC, suggesting that targeting MYO6 may be beneficial for ENZ-resistant CRPC therapy through the AR/MYO6/FAK signaling pathway.
恩扎卢胺（Enz）耐药是去势抵抗性前列腺癌（CRPC）患者预后不良的一个因素，这通常涉及雄激素受体（AR）的异常表达。肌球蛋白 VI（MYO6）是肌球蛋白家族的一个成员，在调节细胞存活方面发挥着重要作用，在前列腺癌（PCa）中高度表达。然而，MYO6 是否参与 CRPC 中的 Enz 耐药以及其机制尚不清楚。
利用多个公开访问的数据库来研究 MYO6 表达与 PCa 进展之间的关系，并筛选与 MYO6 调节的 Enz 耐药相关的差异表达基因（DEGs）和潜在信号通路。采用体外和体内肿瘤发生实验来研究 MYO6 对 PCa 细胞生长和 Enz 耐药性的影响。利用人 PCa 组织和相关临床生化数据来确定 MYO6 在促进 PCa 进展和 Enz 耐药性方面的作用。研究了 MYO6 调节 CRPC 中的基因表达、PCa 进展和 Enz 耐药性的分子机制。
MYO6 在 PCa 患者中的表达增加，并且与 PCa 细胞系和组织中的 AR 表达呈正相关。AR 的过表达增加了 MYO6 的表达，促进了 PCa 细胞的增殖、迁移和侵袭，并抑制了 PCa 细胞的凋亡；而 MYO6 表达的下调则逆转了这些结果，并增强了 Enz 在抑制体外和体内敏感和耐药性 PCa 细胞增殖方面的功能。在机制上，AR 直接结合 MYO6 基因启动子区域（-503 到-283 碱基对）并促进其转录。此外，MYO6 通过整合素β 8（ITGB8）调节激活粘着斑激酶（FAK）酪氨酸 397 磷酸化，从而促进 PCa 进展和 Enz 耐药性。值得注意的是，粘着斑激酶（FAK）抑制剂 Y15 抑制 FAK 的活性可以使 CRPC 细胞对 Enz 治疗重新敏感，在细胞系和小鼠异种移植模型中均如此。
MYO6 在 CRPC 中具有促肿瘤和 Enz 耐药的作用，提示通过 AR/MYO6/FAK 信号通路靶向 MYO6 可能有益于 ENZ 耐药性 CRPC 的治疗。
