| RRC ID |
59676
|
| 著者 |
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.
|
| タイトル |
MDH1 and MPP7 Regulate Autophagy in Pancreatic Ductal Adenocarcinoma.
|
| ジャーナル |
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.
|
| 巻・号 |
79(8)
|
| ページ |
1884-1898
|
| 公開日 |
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
YAP-Signaling Proteins
|
| IF |
8.378
|
| 引用数 |
4
|
| リソース情報 |
| ヒト・動物細胞 |
KLM-1(RCB2138)
KP4-3(RCB1008)
PK-1(RCB1972)
PK-45H(RCB1973) |
