Oxaliplatin resistance in colorectal cancer cells is mediated via activation of ABCG2 to alleviate ER stress induced apoptosis

• Published in: Journal of cellular physiology Vol. 233; no. 7; pp. 5458 - 5467
• Main Authors: Hsu, Hsi‐Hsien, Chen, Ming‐Cheng, Baskaran, Rathinasamy, Lin, Yueh‐Min, Day, Cecilia H., Lin, Yi‐Jiun, Tu, Chuan‐Chou, Vijaya Padma, Viswanadha, Kuo, Wei‐Wen, Huang, Chih‐Yang
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-07-2018
• Subjects: ABCG2; Animals; Apoptosis; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; Biomarkers, Tumor - genetics; Cancer; cancer stem cell; Cell Proliferation - genetics; Chemotherapy; Colon; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Drug resistance; Drug Resistance, Neoplasm - genetics; Endoplasmic Reticulum Stress - genetics; Exposure; G2 phase; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; In vivo methods and tests; Inhibitors; Intracellular signalling; Markers; Metastases; Mice; mRNA; multi drug resistance; Multidrug resistance; Neoplasm Proteins - genetics; Oxaliplatin; Oxaliplatin - administration & dosage; Oxaliplatin - adverse effects; Phosphorylation; Platinum; Proteins; Stresses; Verapamil; Xenograft Model Antitumor Assays; oxaliplatin; cancer stem cell; colon cancer; ABCG2; multi drug resistance
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.26406

Oxaliplatin (OXA), is a third generation platinum drug used as first‐line chemotherapy in colorectal cancer (CRC). Cancer cells acquires resistance to anti‐cancer drug and develops resistance. ATP‐binding cassette (ABC) drug transporter ABCG2, one of multidrug resistance (MDR) protein which can effectively discharge a wide spectrum of chemotherapeutic agents out of cancer cells and subsequently reduce the intracellular concentration of these drugs. Role of ABCG2 and plausible molecular signaling pathways involved in Oxaliplatin‐Resistant (OXA‐R) colon cancer cells was evaluated in the present study. OXA resistant LoVo cells was developed by exposing the colon cells to OXA in a dose‐dependent manner. Development of multi drug resistance in OXA‐R cells was confirmed by exposing the resistance cells to oxaliplatin, 5‐FU, and doxorubicin. OXA treatment resulted in G2 phase arrest in parental LoVo cells, which was overcome by OXA‐R LoVo cells. mRNA and protein expression of ABCG2 and phosphorylation of NF‐κB was significantly higher in OXA‐R than parental cells. Levels of ER stress markers were downregulated in OXA‐R than parental cells. OXA‐R LoVo cells exposed to NF‐κB inhibitor QNZ effectively reduced the ABCG2 and p‐NF‐κB expression and increased ER stress marker expression. On other hand, invasion and migratory effect of OXA‐R cells were found to be decreased, when compared to parental cells. Metastasis marker proteins also downregulated in OXA‐R cells. ABCG2 inhibitor verapamil, downregulate ABCG2, induce ER stress markers and induces apoptosis. In vivo studies in nude mice also confirms the same.
Present study was designed to evaluate plausible role of ABCG2, multi drug resistance protein and associated pathway involved in OXA‐R LoVo cells. Our data show that oxaliplatin resistant LoVo colon cells are resistant to oxaliplatin, 5‐FU, and doxorubicin. Multi drug resistance acquired by overexpression of ABCG2 and p‐NF‐κB and downregulation of ER stress protein thereby preventing apoptosis.