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Oxaliplatin resistance in colorectal cancer cells is mediated via activation of ABCG2 to alleviate ER stress induced apoptosis
Author(s) -
Hsu HsiHsien,
Chen MingCheng,
Baskaran Rathinasamy,
Lin YuehMin,
Day Cecilia H.,
Lin YiJiun,
Tu ChuanChou,
Vijaya Padma Viswanadha,
Kuo WeiWen,
Huang ChihYang
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26406
Subject(s) - abcg2 , oxaliplatin , apoptosis , cancer research , colorectal cancer , cancer cell , cancer , doxorubicin , drug resistance , biology , chemistry , pharmacology , medicine , chemotherapy , atp binding cassette transporter , transporter , biochemistry , gene , microbiology and biotechnology
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.