Thebault Stephanie, Flourakis Matthieu, Vanoverberghe Karine, Vandermoere Franck, Roudbaraki Morad, Lehen'kyi V'yacheslav, Slomianny Christian, Beck Benjamin, Mariot Pascal, Bonnal Jean-Louis, Mauroy Brigitte, Shuba Yaroslav, Capiod Thierry, Skryma Roman, Prevarskaya Natalia
Laboratoire de Physiologie Cellulaire, Institut National de la Sante et de la Recherche Medicale, Centre National de la Recherche Scientifique, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France.
Cancer Res. 2006 Feb 15;66(4):2038-47. doi: 10.1158/0008-5472.CAN-05-0376.
One major clinical problem with prostate cancer is the cells' ability to survive and proliferate upon androgen withdrawal. Because Ca2+ is central to growth control, understanding the mechanisms of Ca2+ homeostasis involved in prostate cancer cell proliferation is imperative for new therapeutic strategies. Here, we show that agonist-mediated stimulation of alpha1-adrenergic receptors (alpha1-AR) promotes proliferation of the primary human prostate cancer epithelial (hPCE) cells by inducing store-independent Ca2+ entry and subsequent activation of nuclear factor of activated T cells (NFAT) transcription factor. Such an agonist-induced Ca2+ entry (ACE) relied mostly on transient receptor potential canonical 6 (TRPC6) channels, whose silencing by antisense hybrid depletion decreased both hPCE cell proliferation and ACE. In contrast, ACE and related growth arrest associated with purinergic receptors (P2Y-R) stimulation involved neither TRPC6 nor NFAT. Our findings show that alpha1-AR signaling requires the coupled activation of TRPC6 channels and NFAT to promote proliferation of hPCE cells and thereby suggest TRPC6 as a novel potential therapeutic target.
前列腺癌的一个主要临床问题是细胞在雄激素撤除后仍具有存活和增殖的能力。由于Ca2+对于生长控制至关重要，因此了解前列腺癌细胞增殖过程中涉及的Ca2+稳态机制对于新的治疗策略来说势在必行。在此，我们表明，激动剂介导的α1-肾上腺素能受体（α1-AR）刺激通过诱导不依赖于内质网钙库的Ca2+内流以及随后激活活化T细胞核因子（NFAT）转录因子，从而促进原代人前列腺癌上皮（hPCE）细胞的增殖。这种激动剂诱导的Ca2+内流（ACE）主要依赖于瞬时受体电位阳离子通道亚家族C成员6（TRPC6）通道，通过反义杂交缺失使其沉默会降低hPCE细胞增殖和ACE。相反，与嘌呤能受体（P2Y-R）刺激相关的ACE和相关生长停滞既不涉及TRPC6也不涉及NFAT。我们的研究结果表明，α1-AR信号传导需要TRPC6通道和NFAT的偶联激活来促进hPCE细胞的增殖，从而提示TRPC6作为一种新的潜在治疗靶点。
