Phospholipase D-mediated autophagic regulation is a potential target for cancer therapy.
Cell Death Differ
; 21(4): 533-46, 2014 Apr.
Article
in En
| MEDLINE
| ID: mdl-24317201
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phospholipase D
/
Autophagy
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Death Differ
Year:
2014
Document type:
Article