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

Abstract

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.

DSTYK Promotes Metastasis and Chemoresistance via EMT in Colorectal Cancer

“…Furthermore, chemotherapy is the standard first-line treatment option for CRC patients with metastatic unresectable disease ( Van Cutsem et al, 2016 ; Munker et al, 2018 ). OXA has been considered as the first‐line chemotherapeutic drug in colorectal cancer treatment ( Hsu et al, 2018 ). Most therapeutic efforts now are focused on validating a novel potential biomarker of tumor progression or response to drug treatment.…”

<p>FOXC2 Promotes Oxaliplatin Resistance by Inducing Epithelial-Mesenchymal Transition via MAPK/ERK Signaling in Colorectal Cancer</p>

“…A variety of mechanisms, such as ER stress, DNA damage, autophagy and EMT, have been reported to contribute to drug resistance in CRC. [23][24][25][26] In general, EMT is traditionally thought to contribute to tumor invasion and metastasis. In recent years, accumulated evidence has indicated that EMT plays an essential role in the regulation of drug sensitivity in some human malignant cancers.…”

MicroRNAs as potential therapeutic targets to predict responses to oxaliplatin in colorectal cancer: From basic evidence to therapeutic implication

“…Another ABC transporter is ABCG2, which has been identified as a molecular cause of MDR in diverse cancer cells . The activation of ABCG2 mediate oxaliplatin resistance in CRC cells . It has been revealed that miR‐142‐3p inhibited the growth of CRC cells in vivo via inhibiting ABCG2 in tumor tissues .…”

“…62 The activation of ABCG2 mediate oxaliplatin resistance in CRC cells. 63 It has been revealed that miR-142-3p inhibited the growth of CRC cells in vivo via inhibiting ABCG2 in tumor tissues. 64 In addition, evidences indicated that miR-328 and miR-519c downregulate ABCG2 expression in CRC cell lines and decrease anticancer drug resistance.…”