Low-dose mono(2-ethylhexyl) phthalate promotes ovarian cancer development through PPARα-dependent PI3K/Akt/NF-κB pathway

Jing Leng; Hongyi Li; Yuequn Niu; Kelie Chen; Xiaoyu Yuan; Hanwen Chen; Zhiqin Fu; Lihuan Zhang; Fang Wang; Chaoyi Chen; Paul Héroux; Jun Yang; Xinqiang Zhu; Weiguo Lu; Dajing Xia; Yihua Wu

doi:10.1016/j.scitotenv.2021.147990

Low-dose mono(2-ethylhexyl) phthalate promotes ovarian cancer development through PPARα-dependent PI3K/Akt/NF-κB pathway

Sci Total Environ. 2021 Oct 10:790:147990. doi: 10.1016/j.scitotenv.2021.147990. Epub 2021 May 24.

Authors

Jing Leng¹, Hongyi Li², Yuequn Niu¹, Kelie Chen¹, Xiaoyu Yuan¹, Hanwen Chen³, Zhiqin Fu⁴, Lihuan Zhang¹, Fang Wang¹, Chaoyi Chen⁵, Paul Héroux⁶, Jun Yang⁷, Xinqiang Zhu⁸, Weiguo Lu¹, Dajing Xia⁹, Yihua Wu¹⁰

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; Scientific Research Department, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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; Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
⁵ Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou 310058, Zhejiang, China.
⁶ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada.
⁷ Department of Public Health, Hangzhou Normal University School of Medicine, Hangzhou, China; Zhejiang Provincial Center for Uterine Cancer Diagnosis and Therapy Research of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁸ Central Laboratory of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China.
⁹ Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: dxia@zju.edu.cn.
¹⁰ 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 (2019RU042), Hangzhou 310058, Zhejiang, China. Electronic address: georgewu@zju.edu.cn.

PMID: 34380243
DOI: 10.1016/j.scitotenv.2021.147990

Abstract

The plasticizer di(2-ethylhexyl) phthalate (DEHP) and its hydrolysate mono(2-ethylhexyl) phthalate (MEHP) are major toxicants from plastics, but their association with hormone-dependent cancers has been controversial. We treated the human ovarian cancer cell lines SKOV3 and A2780 with low concentrations of DEHP/MEHP, and found that although no significant effect on cell proliferation was observed, ovarian cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT) were promoted by submicromolar MEHP but not DEHP. Next, ovarian cancer patient data from The Cancer Genome Atlas (TCGA) were obtained and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) supported enrichment and Kaplan-Meier survival analyses, which identified PI3K/Akt pathway as a pivotal signaling pathway in ovarian cancer. We found that 500 nM MEHP treatment significantly increased PIK3CA expression, which could be reversed by the knockdown of peroxisome proliferator-activated receptor alpha (PPARα). Silencing PIK3CA significantly suppressed the MEHP-induced migration, invasion and EMT. In addition, we validated that MEHP treatment promoted phosphorylation of Akt and degradation of IκB-α, thereby activating NF-κB and enhancing NF-κB nuclear translocation. In nude mice, MEHP exposure significantly promoted the metastasis of ovarian cancer xenografts, which could be suppressed by the treatment of PPARα inhibitor GW6471. Our findings showed that low-dose MEHP promoted ovarian cancer progression through activating PI3K/Akt/NF-κB pathway, in a PPARα-dependent manner.

Keywords: Low-dose exposure; MEHP; Metastasis; Ovarian cancer; PI3K pathway; PPARα.

MeSH terms

Animals
Cell Line, Tumor
Diethylhexyl Phthalate* / analogs & derivatives
Diethylhexyl Phthalate* / toxicity
Female
Humans
Mice
Mice, Nude
NF-kappa B
Ovarian Neoplasms* / chemically induced
PPAR alpha / genetics
Phosphatidylinositol 3-Kinases
Phthalic Acids
Proto-Oncogene Proteins c-akt

Substances

NF-kappa B
PPAR alpha
Phthalic Acids
phthalic acid
Diethylhexyl Phthalate
Proto-Oncogene Proteins c-akt
mono-(2-ethylhexyl)phthalate