Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells
Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells
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DOI：
10.4161/cc.27355
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发表时间：
2014-02-01
期刊：
影响因子：
4.3
通讯作者：
Holz, Marina K.
中科院分区：
文献类型：
--
作者：
Alayev, Anya;Sun, Yang;Holz, Marina K.
哺乳动物/机械靶的雷帕霉素复合体1(MTORC1)信号通路在多种癌症和疾病中被过度激活，包括淋巴管肌瘤病(LAM)和结节性硬化症(TSC)，这些疾病的特征是肿瘤抑制基因TSC1或TSC2突变。使用mTORC1抑制剂，如雷帕霉素或其类似物(Rapalog)，令人担忧的是，它们会导致自噬上调，并抑制Akt的负反馈回路，从而促进细胞存活，导致治疗只有部分有效，停止治疗后会复发。在这项研究中，我们研究了雷帕霉素与白藜芦醇(一种自然产生的多酚)在TSC2缺陷细胞中的使用。我们测试了这种组合是否会阻止雷帕霉素诱导的自噬上调，并将细胞命运转向凋亡。我们发现，这种联合治疗阻断了雷帕霉素诱导的自噬上调，并恢复了对Akt的抑制。有趣的是，雷帕霉素和白藜芦醇的联合使用选择性地促进了TSC2缺陷细胞的凋亡。因此，在雷帕霉素治疗的基础上加用白藜芦醇可能是一种有希望的选择性靶向治疗TSC缺失和mTORC1过度激活的疾病。
The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is hyperactivated in a variety of cancers and disorders, including lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC), which are characterized by mutations in tumor suppressors TSC1 or TSC2. The concern with the use of mTORC1 inhibitors, such as rapamycin or its analogs (rapalogs), is that they cause upregulation of autophagy and suppress the negative feedback loop to Akt, which promotes cell survival, causing the therapy to be only partially effective, and relapse occurs upon cessation of treatment. In this study, we investigate the use of rapamycin in combination with resveratrol, a naturally occurring polyphenol, in TSC2-deficient cells. We tested whether such combination would prevent rapamycin-induced upregulation of autophagy and shift the cell fate toward apoptosis. We found that this combination treatment blocked rapamycin-induced upregulation of autophagy and restored inhibition of Akt. Interestingly, the combination of rapamycin and resveratrol selectively promoted apoptosis of TSC2-deficient cells. Thus, the addition of resveratrol to rapamycin treatment may be a promising option for selective and targeted therapy for diseases with TSC loss and mTORC1 hyperactivation.