HSP60 Regulates Lipid Metabolism in Human Ovarian Cancer.

Na Li,Liang Shen,Yaying Zhang,Siqi Wen,Ligang Xing,Shu Zheng,Qing Liu,Jingru Yang,Biao Li,Xianquan Zhan,Nannan Li,Ammad Ahmad Farooqi

doi:10.1155/2021/6610529

Abstract

Accumulating evidence demonstrates that cancer is an oxidative stress-related disease, and oxidative stress is closely linked with heat shock proteins (HSPs). Lipid oxidative stress is derived from lipid metabolism dysregulation that is closely associated with the development and progression of malignancies. This study sought to investigate regulatory roles of HSPs in fatty acid metabolism abnormality in ovarian cancer. Pathway network analysis of 5115 mitochondrial expressed proteins in ovarian cancer revealed various lipid metabolism pathway alterations, including fatty acid degradation, fatty acid metabolism, butanoate metabolism, and propanoate metabolism. HSP60 regulated the expressions of lipid metabolism proteins in these lipid metabolism pathways, including ADH5, ECHS1, EHHADH, HIBCH, SREBP1, ACC1, and ALDH2. Further, interfering HSP60 expression inhibited migration, proliferation, and cell cycle and induced apoptosis of ovarian cancer cells in vitro. In addition, mitochondrial phosphoproteomics and immunoprecipitation-western blot experiments identified and confirmed that phosphorylation occurred at residue Ser70 in protein HSP60, which might regulate protein folding of ALDH2 and ACADS in ovarian cancers. These findings clearly demonstrated that lipid metabolism abnormality occurred in oxidative stress-related ovarian cancer and that HSP60 and its phosphorylation might regulate this lipid metabolism abnormality in ovarian cancer. It opens a novel vision in the lipid metabolism reprogramming in human ovarian cancer.

Highlights

In a biological context, free radical reactive oxygen species (ROS) is a normal byproduct of oxygen metabolism, which plays positive roles in cell signaling and homeostasis [1]
The results found that G0/G1 stage arrest was observed in the si-HSP60 transfection group compared to the control group; namely, the number of cells at the G0/G1 stage was increased and the number of cells at the S stage was decreased in the si-HSP60 group relative to the control group (Figures 3(e) and 3(f))
The results indicated that HSP60-ALDH2 and HSP60-acyl-CoA dehydrogenase (ACADS) might exist in binding sites (Hsp60:4PJ1, ALDH2:3N80, and ACADS:2VIG) (Figures 6(a) and 6(b))

Summary

Introduction

Free radical reactive oxygen species (ROS) is a normal byproduct of oxygen metabolism, which plays positive roles in cell signaling and homeostasis [1]. The dramatically increased ROS levels are related to numerous diseases and degenerative processes, such as autoimmune diseases, cancers, and Alzheimer’s diseases [2]. Mitochondria were one of the crucial places to produce ROS during the oxidative phosphorylation process. When electrons are passed through the electron transport chain via oxidation-reduction reactions across the inner mitochondrial membrane, a few oxygen is incompletely reduced to give the superoxide radical (∙O2−) through a series of proteins, such as complex I and complex III of mitochondria [3]. Cancer cells showed greater ROS stress compared to normal cells, partly due to increased metabolic activity, carcinogenesis stimulation, and mitochondrial malfunction [5]. The previous studies showed that ROS could activate various oncogenic

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