Phospholipase D-mediated autophagic regulation is a potential target for cancer therapy

Y. H. Jang; K. Y. Choi; D. S. Min

doi:10.1038/cdd.2013.174

Phospholipase D-mediated autophagic regulation is a potential target for cancer therapy

Y. H. Jang, K. Y. Choi, D. S. Min

Research output: Contribution to journal › Article › peer-review

40 Citations (Scopus)

Abstract

Autophagy is a catabolic process in which cell components are degraded to maintain cellular homeostasis by nutrient limitations. Defects of autophagy are involved in numerous diseases, including cancer. Here, we demonstrate a new role of phospholipase D (PLD) as a regulator of autophagy. PLD inhibition enhances autophagic flux via ATG1 (ULK1), ATG5 and ATG7, which are essential autophagy gene products critical for autophagosome formation. Moreover, PLD suppresses autophagy by differentially modulating phosphorylation of ULK1 mediated by mTOR and adenosine monophosphate-activated protein kinase (AMPK), and by suppressing the interaction of Beclin 1 with vacuolar-sorting protein 34 (Vps34), indicating that PLD coordinates major players of the autophagic pathway, AMPK-mTOR-ULK1 and Vps34/Beclin 1. Ultimately, PLD inhibition significantly sensitized in vitro and in vivo cancer regression via genetic and pharmacological inhibition of autophagy, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PLD inhibition. Collectively, we show a novel role for PLD in the molecular machinery regulating autophagy.

Original language	English
Pages (from-to)	533-546
Number of pages	14
Journal	Cell Death and Differentiation
Volume	21
Issue number	4
DOIs	https://doi.org/10.1038/cdd.2013.174
Publication status	Published - 2014 Apr

Bibliographical note

Funding Information:
Acknowledgements. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST; No. 2012002009) and a Translational Research Center for Protein Function Control Grant (NSF 2009-0092960). We thank Dr. T Yosihmori (Osaka University), Misushima (Tokyo Medical and Dental University), G Velasco (Complutense University), M Komatsu (Tokyo Metropolitan Institute of Medical Science), M Colombo (Universidad Nacional de Cuyo, Mendoza), M Kundu (St. Jude Children’s Hospital), B Levine (University of Texas Southwestern Medical School), G Paolo (Columbia University) and Marja Jäättelä (Apoptosis Department and Centre for Genotoxic Stress Research, Denmark) for materials.

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/cdd.2013.174

Cite this

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abstract = "Autophagy is a catabolic process in which cell components are degraded to maintain cellular homeostasis by nutrient limitations. Defects of autophagy are involved in numerous diseases, including cancer. Here, we demonstrate a new role of phospholipase D (PLD) as a regulator of autophagy. PLD inhibition enhances autophagic flux via ATG1 (ULK1), ATG5 and ATG7, which are essential autophagy gene products critical for autophagosome formation. Moreover, PLD suppresses autophagy by differentially modulating phosphorylation of ULK1 mediated by mTOR and adenosine monophosphate-activated protein kinase (AMPK), and by suppressing the interaction of Beclin 1 with vacuolar-sorting protein 34 (Vps34), indicating that PLD coordinates major players of the autophagic pathway, AMPK-mTOR-ULK1 and Vps34/Beclin 1. Ultimately, PLD inhibition significantly sensitized in vitro and in vivo cancer regression via genetic and pharmacological inhibition of autophagy, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PLD inhibition. Collectively, we show a novel role for PLD in the molecular machinery regulating autophagy.",

author = "Jang, {Y. H.} and Choi, {K. Y.} and Min, {D. S.}",

note = "Funding Information: Acknowledgements. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST; No. 2012002009) and a Translational Research Center for Protein Function Control Grant (NSF 2009-0092960). We thank Dr. T Yosihmori (Osaka University), Misushima (Tokyo Medical and Dental University), G Velasco (Complutense University), M Komatsu (Tokyo Metropolitan Institute of Medical Science), M Colombo (Universidad Nacional de Cuyo, Mendoza), M Kundu (St. Jude Children{\textquoteright}s Hospital), B Levine (University of Texas Southwestern Medical School), G Paolo (Columbia University) and Marja J{\"a}{\"a}ttel{\"a} (Apoptosis Department and Centre for Genotoxic Stress Research, Denmark) for materials.",

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Phospholipase D-mediated autophagic regulation is a potential target for cancer therapy

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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