Inserm, U1003, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, France.
Oncogene. 2010 Aug 12;29(32):4611-6. doi: 10.1038/onc.2010.210. Epub 2010 Jun 7.
Although the transient receptor potential melastatin 8 (TRPM8) cold receptor is highly expressed in prostate cancer (PCa) and constitutes a promising diagnostic and prognostic indicator, the natural agonists of this channel in the prostate, as well as its physiological and pathological functions, remain unknown. In this study, we identified the well-known PCa marker, prostate-specific antigen (PSA), as a physiological TRPM8 agonist. Electrophysiological and Ca(2+) imaging studies demonstrated that PSA activated TRPM8-mediated current by the bradykinin 2 receptor signaling pathway. Further investigation of this mechanism by cell-surface biotinylation revealed that the increase in TRPM8 current induced by PSA was due to an increase in the number of functional TRPM8 channels on the plasma membrane. Importantly, wound-healing and migration assays revealed that TRPM8 activation by PSA reduced motility of the PC3 PCa cell line, suggesting that plasma membrane TRPM8 has a protective role in PCa progression. Consequently, PSA was identified as a natural TRPM8 agonist in the prostate and we propose a putative physiological role for both of these proteins in carcinogenesis, making this pathway a potentially important target for anticancer agent development.
瞬时受体电位 melastatin 8（TRPM8）冷受体在前列腺癌（PCa）中高度表达，是一种很有前途的诊断和预后标志物，但该通道在前列腺中的天然激动剂及其生理和病理功能仍不清楚。在这项研究中，我们确定了众所周知的前列腺癌标志物前列腺特异性抗原（PSA）是一种生理性的 TRPM8 激动剂。电生理和 Ca(2+)成像研究表明，PSA 通过缓激肽 2 受体信号通路激活 TRPM8 介导的电流。通过细胞膜生物素化进一步研究该机制表明，PSA 诱导的 TRPM8 电流增加是由于质膜上功能性 TRPM8 通道数量的增加。重要的是，划痕愈合和迁移实验表明，PSA 激活 TRPM8 可降低 PC3 PCa 细胞系的运动性，这表明质膜 TRPM8 在前列腺癌进展中具有保护作用。因此，PSA 被鉴定为前列腺中的天然 TRPM8 激动剂，我们提出这两种蛋白在致癌作用中可能具有生理作用，使该途径成为抗癌药物开发的潜在重要靶点。
