Low-dose BPA and its substitute BPS promote ovarian cancer cell stemness via a non-canonical PINK1/p53 mitophagic signaling

Xiaoyu Yuan; Kelie Chen; Fang Zheng; Sinan Xu; Yating Li; Yuwei Wang; Heng Ni; Fang Wang; Zhenyan Cui; Yuheng Qin; Dajing Xia; Yihua Wu

doi:10.1016/j.jhazmat.2023.131288

Low-dose BPA and its substitute BPS promote ovarian cancer cell stemness via a non-canonical PINK1/p53 mitophagic signaling

J Hazard Mater. 2023 Jun 15:452:131288. doi: 10.1016/j.jhazmat.2023.131288. Epub 2023 Mar 24.

Authors

Xiaoyu Yuan¹, Kelie Chen¹, Fang Zheng¹, Sinan Xu¹, Yating Li¹, Yuwei Wang¹, Heng Ni¹, Fang Wang¹, Zhenyan Cui¹, Yuheng Qin¹, Dajing Xia², Yihua Wu³

Affiliations

¹ Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China. Electronic address: dxia@zju.edu.cn.
³ Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China; Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Hangzhou, China. Electronic address: georgewu@zju.edu.cn.

PMID: 36989771
DOI: 10.1016/j.jhazmat.2023.131288

Abstract

The environmental toxicity of bisphenol A (BPA) and its analog like bisphenol S (BPS) have drawn wide attention, but their roles in cancer progression remain controversial. Here, we investigated the effect of BPA/BPS on the development of ovarian cancer. Human internal BPA/BPS exposure levels were analyzed from NHANES 2013-2016 data. We treated human ovarian cancer cells with 0-1000 nM BPA/BPS and found that 100 nM BPA/BPS treatment significantly increased Cancer Stem Cell (CSC) markers expression including OCT4, NANOG and SOX2. Cancer cell stemness evaluation induced by BPA/BPS was notably attenuated by the knockdown of PINK1 or Mdivi-1 treatment. The activation of PINK1 initiated mitophagy by inhibiting p-p53 nuclear translocation in a non-canonical manner. In vivo studies validated that BPA/BPS-exposed mice have higher tumor metastasis incidence compared with the control group, while mitophagy inhibition blocked such a promotion effect. In addition, CSC markers such as SOX2 had been found to be overexpressed in the tumor tissues of BPA/BPS exposure group. Taken together, the findings herein first provide the evidence that environmentally relevant BPA/BPS exposure could enhance ovarian cancer cell stemness through a non-canonical PINK1/p53 mitophagic pathway, raising concerns about the potential population hazards of BPA and other bisphenol analogs.

Keywords: BPA; BPS; Cancer stem cell; Non-canonical mitophagy; Ovarian cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzhydryl Compounds / toxicity
Female
Humans
Mice
Nutrition Surveys
Ovarian Neoplasms*
Protein Kinases
Tumor Suppressor Protein p53* / genetics

Substances

bisphenol A
Tumor Suppressor Protein p53
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
Benzhydryl Compounds
bis(4-hydroxyphenyl)sulfone
Protein Kinases