Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program).
Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program).
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DOI：
10.18632/oncotarget.4836
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Blagosklonny MV
中科院分区：
文献类型：
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作者：
Leontieva OV;Demidenko ZN;Blagosklonny MV
在增殖细胞中，mTOR是活跃的，并促进细胞生长。当细胞周期停滞时，mTOR将可逆停滞转化为衰老（衰老转化）。雷帕霉素和其他雷帕霉素类似物抑制衰老转化，而是维持静止。在这里，我们发现ATP竞争性激酶抑制剂（Torin 1和PP 242），抑制mTORC 1和TORC 2，也抑制老年转换。尽管抑制了增殖（在增殖细胞中），mTOR抑制剂保留了停滞细胞中的再增殖潜力（RP）。在p21停滞的细胞中，Torin 1和PP 242在低至1-3 nM和10-30 nM的浓度下可检测到抑制衰老转化，分别在30 nM和300 nM时达到最大衰老抑制。接近最大的衰老抑制与p-S6 K（T389）和p-S6（S235/236）的抑制一致。双重mTOR抑制剂防止衰老形态和肥大。我们的研究需要调查低剂量的双重mTOR抑制剂是否会延长动物的寿命并延缓年龄相关疾病。可以设想一类新的潜在抗衰老药物。
In proliferating cells, mTOR is active and promotes cell growth. When the cell cycle is arrested, then mTOR converts reversible arrest to senescence (geroconversion). Rapamycin and other rapalogs suppress geroconversion, maintaining quiescence instead. Here we showed that ATP-competitive kinase inhibitors (Torin1 and PP242), which inhibit both mTORC1 and TORC2, also suppressed geroconversion. Despite inhibition of proliferation (in proliferating cells), mTOR inhibitors preserved re-proliferative potential (RP) in arrested cells. In p21-arrested cells, Torin 1 and PP242 detectably suppressed geroconversion at concentrations as low as 1-3 nM and 10-30 nM, reaching maximal gerosuppression at 30 nM and 300 nM, respectively. Near-maximal gerosuppression coincided with inhibition of p-S6K(T389) and p-S6(S235/236). Dual mTOR inhibitors prevented senescent morphology and hypertrophy. Our study warrants investigation into whether low doses of dual mTOR inhibitors will prolong animal life span and delay age-related diseases. A new class of potential anti-aging drugs can be envisioned.