title: AMPK mediates a pro-survival autophagy downstream of PARP-1 activation in response to DNA alkylating agents.
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.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Shukie
authors.initials: S
authors.lastname: Ng
authors.forename: Qing
authors.initials: Q
authors.lastname: Huang
authors.forename: You-Tong
authors.initials: YT
authors.lastname: Wu
authors.forename: Zhengqiu
authors.initials: Z
authors.lastname: Li
authors.forename: Shao Q
authors.initials: SQ
authors.lastname: Yao
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D055786:Gene Knockout Techniques; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics
chemical_list: D000477:Alkylating Agents; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D008769:Methylnitronitrosoguanidine; D000255:Adenosine Triphosphate; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases