AMPK mediates a pro-survival autophagy downstream of PARP-1 activation in response to DNA alkylating agents |
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| Authors: | Jing Zhou Shukie Ng Qing Huang You-Tong Wu Zhengqiu Li Shao Q. Yao Han-Ming Shen |
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| Affiliation: | 1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore;2. Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Republic of Singapore;3. Department of Chemistry, Faculty of Science, National University of Singapore, Singapore 117597, Republic of Singapore;4. Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117597, Republic of Singapore |
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| Abstract: | 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. |
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