High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer.
High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer.
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DOI：
10.18632/oncotarget.14178
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发表时间：
2017-02-21
期刊：
影响因子：
--
通讯作者：
Zakharian E
中科院分区：
文献类型：
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作者：
Asuthkar S;Demirkhanyan L;Mueting SR;Cohen A;Zakharian E
Ca2+ 渗透性离子通道 TRPM8 是前列腺上皮的标志。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细胞中的 Ca2+ 稳态。由于雄激素与前列腺癌的发展密切相关，因此我们的研究评估了新型睾酮受体 TRPM8 在癌症中的作用。尽管TRPM8 mRNA水平在早期前列腺癌阶段增加，但我们发现它并没有成比例地转化为TRPM8蛋白水平。高通量蛋白质组分析表明，人类前列腺癌细胞中 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来执行的。对前列腺癌患者中TRPM8表达模式的评估进一步证实了TRPM8从质膜去除的发生率及其内化模式与肿瘤的严重程度相一致。总之，我们的结果表明，前列腺癌中增强的 TRPM8 水解可以呈现一种适应机制，通过绕过睾酮诱导的 TRPM8 快速 Ca2+ 摄取来维持，从而降低细胞凋亡率。有鉴于此，TRPM8的恢复可能为抗肿瘤防御机制提供一种新的治疗策略。
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.