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

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.

• Authors: Y H Jang, K Y Choi, D S Min
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 21 Issue 4 Pg. 533-46 (Apr 2014) ISSN: 1476-5403 [Electronic] England
• PMID: 24317201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Atg5 protein, mouse
• Atg7 protein, mouse
• Autophagy-Related Protein 5
• BECN1 protein, human
• Beclin-1
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Microtubule-Associated Proteins
• Phosphodiesterase Inhibitors
• MTOR protein, human
• Autophagy-Related Protein-1 Homolog
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• ULK1 protein, human
• AMP-Activated Protein Kinases
• Phospholipase D
• phospholipase D1
• Autophagy-Related Protein 7

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy (drug effects)
• Autophagy-Related Protein 5
• Autophagy-Related Protein 7
• Autophagy-Related Protein-1 Homolog
• Beclin-1
• Cell Line
• HEK293 Cells
• HeLa Cells
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microtubule-Associated Proteins (antagonists & inhibitors, genetics, metabolism)
• Neoplasms (drug therapy)
• Phosphodiesterase Inhibitors (pharmacology, therapeutic use)
• Phospholipase D (antagonists & inhibitors, genetics, metabolism)
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Transplantation, Heterologous