RRC ID 59676
Author New M, Van Acker T, Sakamaki JI, Jiang M, Saunders RE, Long J, Wang VM, Behrens A, Cerveira J, Sudhakar P, Korcsmaros T, Jefferies HBJ, Ryan KM, Howell M, Tooze SA.
Title MDH1 and MPP7 Regulate Autophagy in Pancreatic Ductal Adenocarcinoma.
Journal Cancer Res
Abstract Pancreatic ductal adenocarcinoma (PDAC) is driven by metabolic changes in pancreatic cells caused by oncogenic mutations and dysregulation of p53. PDAC cell lines and PDAC-derived xenografts grow as a result of altered metabolic pathways, changes in stroma, and autophagy. Selective targeting and inhibition of one of these may open avenues for the development of new therapeutic strategies. In this study, we performed a genome-wide siRNA screen in a PDAC cell line using endogenous autophagy as a readout and identified several regulators of autophagy that were required for autophagy-dependent PDAC cell survival. Validation of two promising candidates, MPP7 (MAGUK p55 subfamily member 7, a scaffolding protein involved in cell-cell contacts) and MDH1 (cytosolic Malate dehydrogenase 1), revealed their role in early stages of autophagy during autophagosome formation. MPP7 was involved in the activation of YAP1 (a transcriptional coactivator in the Hippo pathway), which in turn promoted autophagy, whereas MDH1 was required for maintenance of the levels of the essential autophagy initiator serine-threonine kinase ULK1, and increased in the activity upon induction of autophagy. Our results provide a possible explanation for how autophagy is regulated by MPP7 and MDH1, which adds to our understanding of autophagy regulation in PDAC. SIGNIFICANCE: This study identifies and characterizes MPP7 and MDH1 as novel regulators of autophagy, which is thought to be responsible for pancreatic cancer cell survival.
Volume 79(8)
Pages 1884-1898
Published 2019-4-15
DOI 10.1158/0008-5472.CAN-18-2553
PII 0008-5472.CAN-18-2553
PMID 30765601
PMC PMC6522344
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism Apoptosis Autophagy* Autophagy-Related Protein-1 Homolog / genetics Autophagy-Related Protein-1 Homolog / metabolism Carcinoma, Pancreatic Ductal / genetics Carcinoma, Pancreatic Ductal / metabolism Carcinoma, Pancreatic Ductal / pathology* Cell Proliferation Gene Expression Regulation, Neoplastic* Humans Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism Malate Dehydrogenase / antagonists & inhibitors Malate Dehydrogenase / genetics Malate Dehydrogenase / metabolism* Membrane Proteins / genetics Membrane Proteins / metabolism* Pancreatic Neoplasms / genetics Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / pathology* RNA, Small Interfering / genetics Signal Transduction Transcription Factors / genetics Transcription Factors / metabolism Tumor Cells, Cultured
IF 8.378
Times Cited 4
Resource
Human and Animal Cells KLM-1(RCB2138) KP4-3(RCB1008) PK-1(RCB1972) PK-45H(RCB1973)