Zhou 2018 Cell Death Dis
|Zhou C, Sun H, Zheng C, Gao J, Fu Q, Hu N, Shao X, Zhou Y, Xiong J, Nie K, Zhou H, Shen L, Fang H, Lyu J (2018) Oncogenic HSP60 regulates mitochondrial oxidative phosphorylation to support Erk1/2 activation during pancreatic cancer cell growth. Cell Death Dis 9:161.|
Abstract: HSP60 is a mitochondrial localized quality control protein responsible for maintaining mitochondrial function. Although HSP60 is considered both a tumor suppressor and promoter in different types of cancer, the role of HSP60 in human pancreatic ductal adenocarcinoma (PDAC) remains unknown. In this study, we demonstrated that HSP60 was aberrantly expressed in human pancreatic cancer tissues and cell lines. Analysis of the Cancer Genome Atlas database revealed that HSP60 expression is positively correlated with pancreatic cancer. Further, knockdown of HSP60 attenuated pancreatic ductal cancer cell proliferation and migration/invasion, whereas ectopic expression of HSP60 increased tumorigenesis. Using an in vivo tumorigenicity assay, we confirmed that HSP60 promoted the growth of pancreatic ductal cancer cells. Functional analyses demonstrated that HSP60 plays a key role in the regulation of mitochondrial function. Mechanistically, both HSP60 knockdown and oxidative phosphorylation (OXPHOS) inhibition by metformin decreased Erk1/2 phosphorylation and induced apoptosis and cell cycle arrest, whereas Erk1/2 reactivation with EGF promoted cell proliferation. Intriguingly, in vitro ATP supplementation partially restored Erk1/2 phosphorylation and promoted proliferation in PDAC cells with HSP60 knockdown and OXPHOS inhibition. These results suggest that mitochondrial ATP is an important sensor of Erk1/2 regulated apoptosis and the cell cycle in PDAC cells. Thus, our findings indicate for the first time that HSP60 may serve as a novel diagnostic target of human pancreatic cancer, and that inhibition of mitochondrial function using drugs such as metformin may be a beneficial therapeutic strategy targeting pancreatic cancer cells with aberrant function of the HSP60/OXPHOS/Erk1/2 phosphorylation axis.
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Cancer
Organism: Human Tissue;cell: Islet cell;pancreas;thymus, Other cell lines Preparation: Intact cells Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Supercomplex
Coupling state: LEAK, ROUTINE Pathway: ROX HRR: Oxygraph-2k