Remarkable inhibition of mTOR signaling by the combination of rapamycin and 1,4-phenylenebis(methylene)selenocyanate in human prostate cancer cells.
Remarkable inhibition of mTOR signaling by the combination of rapamycin and 1,4-phenylenebis(methylene)selenocyanate in human prostate cancer cells.
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DOI：
10.1002/ijc.27468
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发表时间：
2012-11-01
影响因子：
6.4
通讯作者：
Sinha, Raghu
中科院分区：
文献类型：
--
作者：
Facompre, Nicole D.;Sinha, Indu;El-Bayoumy, Karam;Pinto, John T.;Sinha, Raghu
临床前研究和临床分析表明，哺乳动物雷帕霉素靶蛋白（mTOR）通路在前列腺癌的进展中起作用，这表明mTOR是新疗法的潜在靶点。mTOR是一种丝氨酸/苏氨酸激酶，属于两种不同的信号复合物：mTORC 1和mTORC 2。我们先前表明，合成的有机硒化合物p-XSC有效地抑制活力和关键信号分子（例如，雄激素受体，Akt）在雄激素响应性（AR）和雄激素非依赖性（AI）人前列腺癌细胞中的表达。基于其对Akt的抑制，我们假设p-XSC调节激酶的上游调节因子mTORC 2。我们进一步假设，将p-XSC与雷帕霉素（一种mTORC 1抑制剂）结合将是抑制前列腺癌的有效组合策略。在AR LNCaP前列腺癌细胞和AI C4-2和DU 145细胞中检查p-XSC和雷帕霉素单独或组合对活力和mTOR信号传导的影响。通过免疫印迹分析mTORC 1和mTORC 2下游靶标的磷酸化。通过免疫沉淀和免疫印迹来探测mTORC 1和mTORC 2特异性蛋白与mTOR的相互作用。p-XSC抑制mTORC 2下游靶点Akt和PCKα的磷酸化，并降低C4-2细胞中与mTOR共免疫沉淀的mTORC 2特异性蛋白rictor的水平。p-XSC和雷帕霉素的组合比单独的任一种药剂更有效地抑制C4-2、LNCaP和DU 145细胞中的活力和mTOR信号传导。
Preclinical studies and clinical analyses have implicated the mammalian target of rapamycin (mTOR) pathway in the progression of prostate cancer, suggesting mTOR as a potential target for new therapies. mTOR, a serine/threonine kinase, belongs to two distinct signaling complexes: mTORC1 and mTORC2. We previously showed that the synthetic organoselenium compound, p-XSC, effectively inhibits viability and critical signaling molecules (e.g., androgen receptor, Akt) in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. Based on its inhibition of Akt, we hypothesized that p-XSC modulates mTORC2, an upstream regulator of the kinase. We further hypothesized that combining p-XSC with rapamycin, an mTORC1 inhibitor, would be an effective combinatory strategy for the inhibition of prostate cancer. The effects of p-XSC and rapamycin, alone or in combination, on viability and mTOR signaling were examined in AR LNCaP prostate cancer cells and AI C4-2 and DU145 cells. Phosphorylation of downstream targets of mTORC1 and mTORC2 was analyzed by immunoblotting. The interaction of mTORC1- and mTORC2-specific proteins with mTOR was probed through immunoprecipitation and immunoblotting. p-XSC inhibited phosphorylation of mTORC2 downstream targets, Akt and PCKα, and decreased the levels of rictor, an mTORC2-specific protein, co-immunoprecipitated with mTOR in C4-2 cells. The combination of p-XSC and rapamycin more effectively inhibited viability and mTOR signaling in C4-2, LNCaP, and DU145 cells than either agent individually.
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影响因子：
4.3
作者：
Johnston, LJ;Brown, J;Chao, NJ
通讯作者：
Chao, NJ
影响因子：
15.9
作者：
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影响因子：
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作者：
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Breuleux, Madlaina
影响因子：
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作者：
Pinto, John T.;Lee, Jeong-In;Sinha, Raghu;MacEwan, Melanie E.;Cooper, Arthur J. L.
通讯作者：
Cooper, Arthur J. L.
影响因子：
3.8
作者：
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通讯作者：
Koyama H