Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function
Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function
复制标题
DOI：
10.1172/jci30168
复制
发表时间：
2007-06-01
影响因子：
15.9
通讯作者：
Prevarskaya, Natalia
中科院分区：
文献类型：
--
作者：
Bidaux, Gabriel;Flourakis, Matthieu;Prevarskaya, Natalia
近年来，瞬时受体电位美拉他汀成员8 （TRPM8）通道已成为前列腺癌（PCa）中有希望的预后标志物和推测的治疗靶点。然而，在前列腺癌进展过程中，TRPM8的前列腺特异性调控和功能进化机制尚不清楚。据我们所知，我们首次发现只有分泌成熟分化的人前列腺原发性上皮（PrPE）腔细胞表达功能性质膜TRPM8 （(PM)TRPM8）通道。此外，原位PCa获得的PCa上皮细胞具有明显强于正常细胞的（PM） trpm8介导电流。这种（PM）TRPM8活性在失去其腔内分泌表型的去分化PrPE细胞中被废除。然而，我们发现与（PM）TRPM8相反，内质网TRPM8 (ER)TRPM8保留了其作为ER Ca2+释放通道的功能，独立于细胞分化。我们假设ERTRPM8的构成活性可能是由于截断的TRPM8剪接变体的表达。我们的研究提供了TRPM8在PCa进展中的作用，并表明TRPM8是一个潜在的有吸引力的治疗干预靶点：特异性抑制（ER）TRPM8或（PM）TRPM8可能是有用的，这取决于靶向PCa的分期和雄激素敏感性。
In recent years, the transient receptor potential melastatin member 8 (TRPM8) channel has emerged as a promising prognostic marker and putative therapeutic target in prostate cancer (PCa). However, the mechanisms of prostate-specific regulation and functional evolution of TRPM8 during PCa progression remain unclear. Here we show, for the first time to our knowledge, that only secretory mature differentiated human prostate primary epithetial (PrPE) luminal cells expressed functional plasma membrane TRPM8 ((PM)TRPM8) channels. Moreover, PCa epithelial cells obtained from in situ PCa were characterized by a significantly stronger (PM)TRPM8-mediated current than that in normal cells. This (PM)TRPM8 activity was abolished in dedifferentiated PrPE cells that had lost their luminal secretory phenotype. However, we found that in contrast to (PM)TRPM8, endoplasmic reticulum TRPM8 ((ER)TRPM8) retained its function as an ER Ca2+ release channel, independent of cell differentiation. We hypothesize that the constitutive activity of ERTRPM8 may result from the expression of a truncated TRPM8 splice variant. Our study provides insight into the role of TRPM8 in PCa progression and suggests that TRPM8 is a potentially attractive target for therapeutic intervention: specific inhibition of either (ER)TRPM8 or (PM)TRPM8 may be useful, depending on the stage and androgen sensitivity of the targeted PCa.