AMPK mediates a pro-survival autophagy downstream of PARP-1 activation in response to DNA alkylating agents

Jing Zhou; Shukie Ng; Qing Huang; You-Tong Wu; Zhengqiu Li; Shao Q Yao; Han-Ming Shen

doi:10.1016/j.febslet.2012.11.018

AMPK mediates a pro-survival autophagy downstream of PARP-1 activation in response to DNA alkylating agents

FEBS Lett. 2013 Jan 16;587(2):170-7. doi: 10.1016/j.febslet.2012.11.018. Epub 2012 Nov 29.

Authors

Jing Zhou¹, Shukie Ng, Qing Huang, You-Tong Wu, Zhengqiu Li, Shao Q Yao, Han-Ming Shen

Affiliation

¹ Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore.

PMID: 23201261
DOI: 10.1016/j.febslet.2012.11.018

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / antagonists & inhibitors
AMP-Activated Protein Kinases / metabolism*
Adenosine Triphosphate / metabolism
Alkylating Agents / pharmacology*
Animals
Autophagy / drug effects*
Autophagy / physiology*
Cell Survival / drug effects
Cell Survival / physiology
Cells, Cultured
Enzyme Activation / drug effects
Gene Knockout Techniques
Methylnitronitrosoguanidine / pharmacology
Mice
Models, Biological
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases / genetics
Poly(ADP-ribose) Polymerases / metabolism*
RNA, Small Interfering / genetics
Signal Transduction
TOR Serine-Threonine Kinases / metabolism
bcl-2 Homologous Antagonist-Killer Protein / deficiency
bcl-2 Homologous Antagonist-Killer Protein / genetics
bcl-2-Associated X Protein / deficiency
bcl-2-Associated X Protein / genetics

Substances

Alkylating Agents
Bak1 protein, mouse
Bax protein, mouse
Poly(ADP-ribose) Polymerase Inhibitors
RNA, Small Interfering
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
Methylnitronitrosoguanidine
Adenosine Triphosphate
Parp1 protein, mouse
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases
mTOR protein, mouse
TOR Serine-Threonine Kinases
AMP-Activated Protein Kinases