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Inhibition of S6K1 enhances glucose deprivation-induced cell death via downregulation of anti-apoptotic proteins in MCF-7 breast cancer cells

机译:抑制S6K1通过下调MCF-7乳腺癌细胞中的抗凋亡蛋白来增强葡萄糖剥夺诱导的细胞死亡

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摘要

Nutrient-limiting conditions are frequently encountered by tumor cells in poorly vascularized microenvironments. These stress conditions may facilitate the selection of tumor cells with an inherent ability to decrease apoptotic potential. Therefore, selective targeting of tumor cells under glucose deprivation conditions may provide an effective alternative strategy for cancer therapy. In the present study, we investigated the effects of S6 kinase 1 (S6K1) inhibition on glucose deprivation-induced cell death and the underlying mechanisms in MCF-7 breast cancer cells. PF4708671, a selective inhibitor of S6K1, and knockdown of S6K1 with specific siRNA enhanced cell death induced under glucose deprivation conditions. Moreover, inhibition of S6K1 led to apoptosis in glucose-starved MCF-7 cells via downregulation of the anti-apoptotic proteins, Mcl-1 and survivin. Further experiments revealed that sorafenib, shown to be involved in Mcl-1 and survivin downregulation via mTOR/S6K1 inhibition significantly promotes cell death under glucose deprivation conditions. These findings collectively suggest that S6K1 plays an important role in tumor cell survival under stress conditions, and thus inhibition of S6K1 may be an effective strategy for sensitizing cells to glucose deprivation. ? 2013 Elsevier Inc.
机译:在血管化不良的微环境中,肿瘤细胞经常遇到营养限制条件。这些应激条件可以促进具有降低凋亡潜力的固有能力的肿瘤细胞的选择。因此,在葡萄糖剥夺条件下选择性靶向肿瘤细胞可以为癌症治疗提供有效的替代策略。在本研究中,我们研究了S6激酶1(S6K1)抑制对葡萄糖剥夺诱导的细胞死亡以及MCF-7乳腺癌细胞潜在机制的影响。 PF4708671(S6K1的选择性抑制剂)以及用特异性siRNA敲低S6K1可以增强在葡萄糖剥夺条件下诱导的细胞死亡。此外,通过下调抗凋亡蛋白Mcl-1和survivin抑制S6K1导致葡萄糖饥饿的MCF-7细胞凋亡。进一步的实验表明,索拉非尼通过抑制mTOR / S6K1参与Mcl-1和survivin下调,从而显着促进葡萄糖剥夺条件下的细胞死亡。这些发现共同表明,S6K1在应激条件下在肿瘤细胞存活中起重要作用,因此抑制S6K1可能是使细胞对葡萄糖缺乏敏感的有效策略。 ? 2013爱思唯尔公司

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