Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.
FEBS Lett. 2013 Jan 16;587(2):170-7. doi: 10.1016/j.febslet.2012.11.018. Epub 2012 Nov 29.
In this study we aim to elucidate the signaling pathway and biological function of autophagy induced by MNNG, a commonly used DNA alkylating agent. We first observed that MNNG is able to induce necrotic cell death and autophagy in Bax-/- Bak-/- double knockout MEFs. We analyzed the critical role of PARP-1 activation and ATP depletion in MNNG-mediated cell death and autophagy via AMPK activation and mTOR suppression. We provide evidence that suppression of AMPK blocks MNNG-induced autophagy and enhances cell death, suggesting the pro-survival function of autophagy in MNNG-treated cells. Taken together, data from this study reveal a novel mechanism in controlling MNNG-mediated autophagy via AMPK activation downstream of PARP-1 activation and ATP depletion.
在这项研究中，我们旨在阐明 MNNG（一种常用的 DNA 烷化剂）诱导的自噬的信号通路和生物学功能。我们首先观察到 MNNG 能够诱导 Bax-/- Bak-/- 双敲除 MEF 细胞发生坏死性细胞死亡和自噬。我们通过 AMPK 激活和 mTOR 抑制分析了 PARP-1 激活和 ATP 耗竭在 MNNG 介导的细胞死亡和自噬中的关键作用。我们提供的证据表明，抑制 AMPK 会阻断 MNNG 诱导的自噬并增强细胞死亡，这表明自噬在 MNNG 处理的细胞中具有促生存功能。综上所述，这项研究的数据揭示了一种通过 PARP-1 激活和 ATP 耗竭下游的 AMPK 激活来控制 MNNG 诱导的自噬的新机制。
