Asuthkar Swapna, Demirkhanyan Lusine, Mueting Samuel Robert, Cohen Alejandro, Zakharian Eleonora
University of Illinois College of Medicine, Department of Cancer Biology and Pharmacology, Peoria, IL 61605, USA.
Proteomics and Mass Spectrometry Core Facility, Life Sciences Research Institute, Dalhousie University, Halifax, NS B3H 4R2, Canada.
Oncotarget. 2017 Feb 21;8(8):12877-12890. doi: 10.18632/oncotarget.14178.
The Ca2+-permeable ion channel TRPM8 is a hallmark of the prostate epithelium. We recently discovered that TRPM8 is an ionotropic testosterone receptor. This finding suggested that testosterone-induced TRPM8 activity regulates Ca2+ homeostasis in the prostate epithelium. Since androgens are significantly implicated in prostate cancer development, the role of the novel testosterone receptor TRPM8 in cancer was assessed in our study. Although TRPM8 mRNA levels increase at the early prostate cancer stages, we found that it is not proportionally translated into TRPM8 protein levels. High-throughput proteome analysis revealed that TRPM8 degradation is enhanced in human prostate cancer cells. This degradation is executed via a dual degradation mechanism with the involvement of both lysosomal and proteasomal proteolytic pathways. The evaluation of the TRPM8 expression pattern in prostate cancer patients further confirmed the incidence of TRPM8 removal from the plasma membrane and its internalization pattern coincided with the severity of the tumor. Together, our results indicate that enhanced TRPM8 hydrolysis in prostate cancer could present an adaptation mechanism, sustained via bypassing testosterone-induced rapid Ca2+ uptake through TRPM8, thus, diminishing the rates of apoptosis. In this light, recovery of TRPM8 may pose a novel therapeutic strategy for an anti-tumor defense mechanism.
钙离子通透离子通道TRPM8是前列腺上皮的一个标志。我们最近发现TRPM8是一种离子型睾酮受体。这一发现表明，睾酮诱导的TRPM8活性调节前列腺上皮中的钙离子稳态。由于雄激素与前列腺癌的发展密切相关，我们在研究中评估了新型睾酮受体TRPM8在癌症中的作用。尽管在前列腺癌早期阶段TRPM8 mRNA水平会升高，但我们发现其并未按比例转化为TRPM8蛋白水平。高通量蛋白质组分析显示，在人前列腺癌细胞中TRPM8的降解增强。这种降解是通过溶酶体和蛋白酶体蛋白水解途径参与的双重降解机制进行的。对前列腺癌患者TRPM8表达模式的评估进一步证实了TRPM8从质膜上移除的发生率，并且其内化模式与肿瘤的严重程度相符。总之，我们的结果表明，前列腺癌中TRPM8水解增强可能是一种适应机制，通过绕过睾酮诱导的TRPM8快速钙离子摄取得以维持，从而降低凋亡率。有鉴于此，恢复TRPM8可能为抗肿瘤防御机制提供一种新的治疗策略。
