Abstract
Multidrug resistance remains a major obstacle to effective chemotherapy of colon cancer. ABCG2, as a half-transporter of the G subfamily of ATP-binding cassette transporter genes (ABC transporters), is known to play a crucial role in multidrug resistance. However, the molecular mechanism of controlling ABCG2 expression in drug resistance of colon cancer is unclear and scarcely reported. In the present study, we systematically investigate the potential role of the c-Jun NH2-terminal kinase (JNK) signal pathway in ABCG2-induced multidrug resistance in colon cancer. In the hydroxycamptothecin (HCPT) resistant cell line SW1116/HCPT from human colon cancer cell line SW1116, ABCG2 is the major factor for multidrug resistance, other than well-studied ABCB1 or ABCC1. Our findings indicate that blocking the JNK pathway by pathway inhibitor SP600125 reduces the expression level and transport function of ABCG2 in drug-resistant cells SW116/HCPT. Notably, the experiments of small interfering RNA directed against JNK1 and JNK2 show that only silence of JNK1 gene has the equal effect as SP600125 on dephosphorylation of transcription factor c-Jun and the expression of ABCG2 protein, while the corresponding phenomena were not observed after silence of JNK2 gene. Meanwhile, SP600125 induces the apoptosis of SW116/HCPT cells by promoting the cleavage of PARP and suppressing the anti-apoptotic protein survivin and bcl-2, and increases the sensitivity of SW1116/HCPT to HCPT. Taken together, our work demonstrated that JNK1/c-jun signaling pathway was involved in ABCG2-mediated multidrug resistance in colon cancer cells. Definitely, inhibition of the JNK1/c-jun pathway is useful for reversing ABCG2-mediated drug resistance in HCPT-resistant colon cancer cells.
Highlights
Multidrug resistance, by which cells resist many structurally and functionally unrelated drugs, is a major obstacle to effective chemotherapy of cancer
The effective chemotherapy is severely limited by multidrug resistance for patients who suffer from malignant tumors, Figure 4
Overexpression of ABCG2 can result in the acquisition of multidrug resistance to multiple anticancer drugs [7,8]
Summary
By which cells resist many structurally and functionally unrelated drugs, is a major obstacle to effective chemotherapy of cancer. As well as to the wellstudied multidrug resistant protein P-glycoprotein(ABCB1), the overexpression of ABCG2 results in cancer cells resistant to various chemotherapeutic drugs by extruding these compounds out of the cells, such as topotecan and methotrexate [7,8]. Both the gene chip and the real-time PCR results based on the SW1116/HCPT cells indicated that the expression of ABCG2 increased significantly in contrast with the parental SW1116 cells [9]. The mRNA expression of ABCG2 in the SW1116/HCPT cells enhanced more than 200 times in contrast with the parental SW1116 cells, while other transporters such as ABCB1, ABCC2, ABCC3 and ABCC6, increased only 0.5–1.0 times. The molecular mechanism of ABCG2 expression and regulation in drug resistance is not clear and unanswered
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
