Methylseleninic acid elevates REDD1 and inhibits prostate cancer cell growth despite AKT activation and mTOR dysregulation in hypoxia.
Methylseleninic acid elevates REDD1 and inhibits prostate cancer cell growth despite AKT activation and mTOR dysregulation in hypoxia.
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DOI：
10.1002/cam4.198
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发表时间：
2014-04
期刊：
影响因子：
4
通讯作者：
Sinha, Raghu
中科院分区：
文献类型：
--
作者：
Sinha, Indu;Allen, Joshua E.;Pinto, John T.;Sinha, Raghu
甲基硒酸（MSeA）是一种单甲基硒代谢物，理论上来源于膳食硒-甲基硒代半胱氨酸的后续β-裂解酶或转氨反应，通过抑制多种癌症的细胞增殖具有强效抗肿瘤活性。我们以前的研究表明，MSeA通过下调缺氧诱导因子HIF-1α促进侵袭性前列腺癌细胞凋亡。我们现在已经扩展了这些研究，以评估MSeA对REDD 1（一种mTOR抑制剂）在缺氧条件下诱导侵袭性前列腺癌细胞死亡的影响。在PTEN+和PTEN−前列腺癌细胞中，我们发现MSeA在缺氧时升高REDD 1和AKT沿着与p70 S6 K的磷酸化。此外，MSeA诱导的REDD 1不依赖于AKT，并且前列腺癌细胞中的mTOR抑制导致对缺氧中MSeA诱导的生长减少的部分抗性。我们的数据表明，MSeA诱导REDD 1和抑制前列腺癌细胞生长在缺氧，尽管激活AKT和mTOR的失调。MSeA升高REDD 1和AKT以促进缺氧中侵袭性前列腺癌细胞的细胞死亡。
Methylseleninic acid (MSeA) is a monomethylated selenium metabolite theoretically derived from subsequent β-lyase or transamination reactions of dietary Se-methylselenocysteine that has potent antitumor activity by inhibiting cell proliferation of several cancers. Our previous studies showed that MSeA promotes apoptosis in invasive prostate cancer cells in part by downregulating hypoxia-inducible factor HIF-1α. We have now extended these studies to evaluate the impact of MSeA on REDD1 (an mTOR inhibitor) in inducing cell death of invasive prostate cancer cells in hypoxia. In both PTEN+ and PTEN− prostate cancer cells we show that MSeA elevates REDD1 and phosphorylation of AKT along with p70S6K in hypoxia. Furthermore, REDD1 induction by MSeA is independent of AKT and the mTOR inhibition in prostate cancer cells causes partial resistance to MSeA-induced growth reduction in hypoxia. Our data suggest that MSeA induces REDD1 and inhibits prostate cancer cell growth in hypoxia despite activation of AKT and dysregulation of mTOR. MSeA elevates REDD1 and AKT to promote cell death in invasive prostate cancer cells in hypoxia.
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发表时间：
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影响因子：
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