TRPV1/CAPN通路与ARV7交互对话在辣椒素抑制前列腺癌恩杂鲁胺耐药作用中的研究

Enzalutamide is a potent drug for treatment of castration resistant prostate cancer (CRPC), but most patients develop resistance eventually. ARV7 is a key protein and drug development target for enzalutamide resistance, and its upstream regulatory mechanisms have not been fully elucidated. Capsaicin is an active substance extracted from natural peppers. Our previous experiments found capsaicin could inhibit enzalutamide resistance via downregulating ARV7, but mechanism remains unclear. Therefore, we proposed that capsaicin overcome enzalutamide resistance mediated by interactive cross-talk between TRPV1/CAPN pathway and ARV7. This study intends to further confirm the inhibitory effect of capsaicin on enzalutamide resistance, then clarify the direct interaction between TRPV1/CAPN pathway and ARV7, and finally demonstrate the molecular mechanism of inhibition function of capsaicin on prostate cancer enzalutamide resistance by in vitro and vivo experiments. This study will provide new ideas for overcoming enzalutamide resistance, and offer new experimental evidence for the application of capsaicin in prostate cancer.

恩杂鲁胺是治疗去势抵抗性前列腺癌（CRPC）的有效药物，但大多数患者最终会产生耐药性。ARV7是导致恩杂鲁胺耐药的关键蛋白和药物研发靶点，其上游调控机制尚未完全阐明。辣椒素是从天然辣椒中提取的活性物质，前期实验发现辣椒素有下调ARV7抑制恩杂鲁胺耐药的潜能，但机制不清。综合前期研究结果，我们提出“TRPV1/CAPN通路与ARV7交互对话介导辣椒素抑制恩杂鲁胺耐药”的科学假设。本研究将在细胞、分子和动物层面上明确辣椒素对恩杂鲁胺耐药的抑制作用；阐明TRPV1/CAPN通路与ARV7之间的直接作用关系；最终论证辣椒素抑制恩杂鲁胺耐药的分子机制。本研究将为克服恩杂鲁胺耐药提供新的研究思路，同时为辣椒素在前列腺癌中的研发和应用提供新的实验依据。

前列腺癌恩杂鲁胺耐药是临床治疗的难点问题，ARV7是重要致病因素。我们前期研究发现辣椒素有下调ARV7抑制恩杂鲁胺耐药的潜能，但机制不清。因此，我们提出“TRPV1/CAPN通路与ARV7交互对话介导辣椒素抑制恩杂鲁胺耐药”。围绕这一科学假设，我们开展了相关研究，发现辣椒素能通过诱导周期阻滞抑制前列腺癌细胞生长；辣椒素与恩杂鲁乱联合应用显著抑制ARV7阳性的去势抵抗性前列腺癌细胞增殖；TRPV1/CAPN通路介导了辣椒素下调ARV7、增强恩杂鲁胺治疗效果的过程。作为本课题的延伸，我们采用基于医学大数据的多组学分析技术鉴定了前列腺癌恩杂鲁胺耐药的关键基因，以及TRPV1与肾癌预后和免疫浸润的关系。