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

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

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40 Citations (Scopus)


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 languageEnglish
Pages (from-to)533-546
Number of pages14
JournalCell Death and Differentiation
Issue number4
Publication statusPublished - 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


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