Calcium Channel CaT 1 in Prostate Cancer Prevention

描述（由申请人提供）： 前列腺癌是西方国家男性癌症相关死亡的主要原因之一。通过营养调整进行初级预防的战略最近已成为一个主要焦点。有大量的流行病学证据表明，主要来自饮食来源的过量膳食钙会增加患前列腺癌的风险。然而，其确切的生物学基础尚不清楚。一种可能的解释是，钙可以降低身体中1，25-维生素D3的水平，维生素D3已被证明可以保护前列腺，但许多科学家质疑这一概念的重要性。了解钙离子通道的分子特性，包括1，25-维生素D3对其的调节，可能有助于解释营养钙在前列腺癌发展中的作用。钙离子通道在前列腺癌上皮细胞的代谢中起着重要作用，但对它们在前列腺癌发生发展中的作用知之甚少。我们建议研究上皮钙进入通道，CaT 1（TRPV 6），和其他钙渗透通道在前列腺癌恶性肿瘤中的作用。我们的实验室最近证明，CaT 1在前列腺恶性肿瘤中上调了几倍，表明它可能参与增殖和肿瘤细胞生长。为了探讨饮食钙、钙通道与前列腺癌的关系，我们拟研究以下几个方面：（1）不同前列腺癌细胞系、对照小鼠前列腺和TRAMP（transgenic adenocarcinoma of mouse prostate）小鼠前列腺癌组织中CaT 1对高钙和低钙饮食反应的调节。 (2)通过将TRAMP小鼠与CaT 1（+/-）或CaT 1（-/-）小鼠杂交，观察CaT 1表达降低对肿瘤进展的影响。(3)CaT 1表达水平对前列腺癌细胞增殖和凋亡的调控作用(4)其他钙通道蛋白的分子特性、生物物理特性及其在前列腺肿瘤进展中的作用。由于人体依赖膳食钙的摄入来维持骨骼的完整性，因此限制膳食钙的摄入并不适合降低患前列腺癌的风险。然而，CaT 1和相关钙通道的分子特征可能导致前列腺癌治疗的替代策略，包括抑制钙流入前列腺癌细胞以损害肿瘤生长。

DESCRIPTION (provided by applicant): Prostate cancer is among the leading causes of cancer-related death of men in Western countries. Strategies for its primary prevention through nutritional modifications have recently become a major focus. There is substantial epidemiologic evidence that an excess of dietary calcium, mainly from dietary sources, increases the risk of prostate cancer. The exact biological basis for this, however, is unknown. One possible explanation is that calcium can reduce the body's level of 1,25-vitamin D3 which has been shown to protect the prostate, but various scientists have questioned the significance of this concept. Understanding the molecular properties of calcium channels, including their regulation by 1,25-vitamin D3, may help explain the role of the nutrient calcium in prostate cancer development. Calcium channels play a important roles in the metabolism of prostate cancer epithelial cells but little is known about their implications in prostate cancer development. We propose to investigate the role of the epithelial calcium entry channel, CaT1 (TRPV6), and other calcium permeable channels in prostate cancer malignancy. Our laboratory has recently demonstrated that CaT1 is upregulated several fold in prostate malignancy, indicating that it might be involved in proliferation and tumor cell growth. To investigate the relationship of dietary calcium, calcium channels and prostate cancer risk, we propose to study the following: (1) The regulation of CaT1 in response to high and low calcium diets in various prostate cancer cell lines, the prostates of control mice and the prostate carcinomas of TRAMP (transgenic adenocarcinoma of mouse prostate) mice. (2) The effect of reduced expression of CaT1 on tumor progression by crossing the TRAMP mouse with the CaT1 (+/-) or CaT1 (-/-) mouse. (3) The implication of the level of CaT1 expression in regulating proliferation and apoptosis in prostate cancer cells. (4) The molecular identity, biophysical properties and roles in prostate tumor progression of other putative calcium channel proteins. Since the human body depends on dietary calcium intake to maintain the integrity of the skeleton, dietary calcium restriction would not be appropriate to reduce the risk of prostate cancer. The molecular characterization of CaT1 and related calcium channels, however, may lead to alternative strategies for the treatment of prostate cancer, involving inhibition of calcium influx into prostate cancer cells to impair tumor growth.