Chen, HP; Lee, YK; Huang, SY; Shi, PC; Hsu, PC; Chang, CF
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.
Colon cancer; DEHP; Drug resistance; MEHP; Phthalates; ABC transporter subfamily B; beta catenin; CD133 antigen; glycogen synthase kinase 3beta; irinotecan; mitogen activated protein kinase; mono(2 ehylhexyl)phthalate; octamer transcription factor 4; oxaliplatin; phthalic acid; phthalic acid bis(2 ethylhexyl) ester; protein bcl 2; protein kinase B; tariquidar; transcription factor NANOG; transcription factor Sox4; unclassified drug; advanced cancer; Article; blood level; cancer patient; cancer recurrence; cancer resistance; cancer stem cell; cell migration; cell self-renewal; cell viability; clinical outcome; colon cancer cell line; controlled study; correlation analysis; epithelial mesenchymal transition; exposure; human; human cell; metastasis
