Phthalate exposure promotes chemotherapeutic drug resistance in colon cancer cells
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Hsin-Pao Chen2,5,*, Yung-Kuo Lee1,3,*, Shih Yin Huang3, Pei-Chun Shi3, Ping-Chi Hsu5 and Chuan-Fa Chang1,3,4
1Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
2Department of Surgery, E-DA Hospital, I-Shou University, Kaohsiung 824, Taiwan
3Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
4Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
5Department of Safety, Health and Environmental Engineering, National Kaohsiung First University of Science and Technology, Kaohsiung 811, Taiwan
*These authors contributed equally to this work
Chuan-Fa Chang, email: firstname.lastname@example.org
Ping-Chi Hsu, email: email@example.com
Keywords: colon cancer; DEHP; MEHP; drug resistance; phthalates
Received: September 07, 2016 Accepted: September 08, 2017 Published: December 08, 2017
Phthalates are widely used as plasticizers. Humans can be exposed to phthalates through ingestion, inhalation, or treatments that release di(2-ethylhexyl) phthalate (DEHP) and its metabolite, mono(2-ehylhexyl) phthalate (MEHP), into the body from polyvinyl chloride-based medical devices. Phthalate exposure may induce reproductive toxicity, liver damage, and carcinogenesis in humans. This study found that colon cancer cells exposed to DEHP or MEHP exhibited increased cell viability and increased levels of P-glycoprotein, CD133, Bcl-2, Akt, ERK, GSK3β, and β-catenin when treated with oxaliplatin or irinotecan, as compared to control. The P-glycoprotein inhibitor, tariquidar, which blocks drug efflux, reduced the viability of DEHP- or MEHP-treated, anti-cancer drug-challenged cells. DEHP or MEHP treatment also induced colon cancer cell migration and epithelial-mesenchymal transformation. Elevated stemness-related protein levels (β-catenin, Oct4, Sox2, and Nanog) and increased cell sphere sizes indicated that DEHP- or MEHP-treated cells were capable of self-renewal. We also found that serum DEHP concentrations were positively correlated with cancer recurrence. These results suggest phthalate exposure enhances colon cancer cell metastasis and chemotherapeutic drug resistance by increasing cancer cell stemness, and that P-glycoprotein inhibitors might improve outcomes for advanced or drug-resistant colon cancer patients.
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