Prevarskaya Natalia, Zhang Lei, Barritt Greg
Inserm, U800, Equipe Labellisee par la Ligue Contre le Cancer, Villeneuve d'Ascq F-59650, France.
Biochim Biophys Acta. 2007 Aug;1772(8):937-46. doi: 10.1016/j.bbadis.2007.05.006. Epub 2007 Jun 2.
The progression of cells from a normal differentiated state in which rates of proliferation and apoptosis are balanced to a tumorigenic and metastatic state involves the accumulation of mutations in multiple key signalling proteins and the evolution and clonal selection of more aggressive cell phenotypes. These events are associated with changes in the expression of numerous other proteins. This process of tumorigenesis involves the altered expression of one or more TRP proteins, depending on the nature of the cancer. The most clearly described changes are those involving TRPM8, TRPV6 and TRPM1. Expression of TRPM8 is substantially increased in androgen-dependent prostate cancer cells, but is decreased in androgen independent and metastatic prostate cancer. TRPM8 expression is regulated, in part, by androgens, most likely through androgen response elements in the TRPM8 promoter region. TRPM8 channels are involved in the regulation of cell proliferation and apoptosis. Expression of TRPV6 is also increased in prostate cancer and in a number of other cancers. In contrast to TRPM8, expression of TRPV6 is not directly regulated by androgens. TRPM1 is highly expressed in early stage melanomas but its expression declines with increases in the degree of aggressiveness of the melanoma. The expression of TRPV1, TRPC1, TRPC6, TRPM4, and TRPM5 is also increased in some cancers. The level of expression of TRPM8 and TRPV6 in prostate cancer, and of TRPM1 in melanomas, potentially provides a good prognostic marker for predicting the course of the cancer in individuals. The Drosophila melanogaster, TRPL, and the TRPV1 and TRPM8 proteins, have been used to try to develop strategies to selectively kill cancer cells by activating Ca(2+) and Na(+) entry, producing a sustained increase in the cytoplasmic concentration of these ions, and subsequent cell death by apoptosis and necrosis. TRPV1 is expressed in neurones involved in sensing cancer pain, and is a potential target for pharmacological inhibition of cancer pain in bone metastases, pancreatic cancer and most likely in other cancers. Further studies are required to assess which other TRP proteins are associated with the development and progression of cancer, what roles TRP proteins play in this process, and to develop further knowledge of TRP proteins as targets for pharmaceutical intervention and targeting in cancer.
细胞从增殖和凋亡速率平衡的正常分化状态发展为致瘤性和转移性状态，涉及多个关键信号蛋白中突变的积累以及更具侵袭性的细胞表型的进化和克隆选择。这些事件与许多其他蛋白质表达的变化相关。肿瘤发生过程涉及一种或多种瞬时受体电位（TRP）蛋白的表达改变，具体取决于癌症的性质。描述最清楚的变化是涉及TRPM8、TRPV6和TRPM1的变化。TRPM8在雄激素依赖性前列腺癌细胞中的表达显著增加，但在雄激素非依赖性和转移性前列腺癌中表达降低。TRPM8的表达部分受雄激素调节，很可能是通过TRPM8启动子区域中的雄激素反应元件。TRPM8通道参与细胞增殖和凋亡的调节。TRPV6在前列腺癌和许多其他癌症中的表达也增加。与TRPM8不同，TRPV6的表达不受雄激素直接调节。TRPM1在早期黑色素瘤中高表达，但随着黑色素瘤侵袭程度的增加其表达下降。TRPV1、TRPC1、TRPC6、TRPM4和TRPM5在某些癌症中的表达也增加。前列腺癌中TRPM8和TRPV6的表达水平以及黑色素瘤中TRPM1的表达水平，可能为预测个体癌症进程提供良好的预后标志物。果蝇的TRPL以及TRPV1和TRPM8蛋白已被用于尝试开发策略，通过激活钙离子（Ca(2+)）和钠离子（Na(+)）内流，使这些离子的细胞质浓度持续升高，并随后通过凋亡和坏死导致细胞死亡，从而选择性杀死癌细胞。TRPV1在参与感知癌痛的神经元中表达，是骨转移、胰腺癌以及很可能在其他癌症中进行癌痛药理学抑制的潜在靶点。需要进一步研究以评估哪些其他TRP蛋白与癌症的发生和发展相关，TRP蛋白在此过程中发挥什么作用，并进一步了解TRP蛋白作为癌症药物干预和靶向治疗靶点的相关知识。
