The c‐MYC‐ABCB5 axis plays a pivotal role in 5‐fluorouracil resistance in human colon cancer cells

• Published in: Journal of cellular and molecular medicine 2015-07, Vol.19 (7), p.1569-1581
• Main Authors: Kugimiya, Naruji, Nishimoto, Arata, Hosoyama, Tohru, Ueno, Koji, Enoki, Tadahiko, Li, Tao‐Sheng, Hamano, Kimikazu
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; 5‐fluorouracil resistance; ABC transporters; ABCB5; Aged; Animal models; Animals; Apoptosis; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cancer therapies; Carcinogenesis - drug effects; Carcinogenesis - pathology; Cell cycle; Cell Line, Tumor; Cell proliferation; Chemotherapy; Chemotherapy, Adjuvant; Chromatin; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colonic Neoplasms - surgery; Colorectal cancer; Colorectal carcinoma; c‐MYC; Drug resistance; Drug Resistance, Neoplasm - drug effects; Female; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Genomic instability; Humans; Immortalization; Immunoprecipitation; Male; Medical prognosis; Mice, Inbred BALB C; Mice, Nude; Myc protein; Neoplasm Recurrence, Local - pathology; Original; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction - drug effects; Survival; Thiazoles - pharmacology; Tumorigenicity; Xenografts
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.12531

c‐MYC overexpression is frequently observed in various cancers including colon cancer and regulates many biological activities such as aberrant cell proliferation, apoptosis, genomic instability, immortalization and drug resistance. However, the mechanism by which c‐MYC confers drug resistance remains to be fully elucidated. In this study, we found that the c‐MYC expression level in primary colorectal cancer tissues correlated with the recurrence rate following 5‐fluorouracil (5‐FU)‐based adjuvant chemotherapy. Supporting this finding, overexpression of exogenous c‐MYC increased the survival rate following 5‐FU treatment in human colon cancer cells, and knockdown of endogenous c‐MYC decreased it. Furthermore, c‐MYC knockdown decreased the expression level of ABCB5, which is involved in 5‐FU resistance. Using a chromatin immunoprecipitation assay, we found that c‐MYC bound to the ABCB5 promoter region. c‐MYC inhibitor (10058‐F4) treatment inhibited c‐MYC binding to the ABCB5 promoter, leading to a decrease in ABCB5 expression level. ABCB5 knockdown decreased the survival rate following 5‐FU treatment as expected, and the ABCB5 expression level was increased in 5‐FU‐resistant human colon cancer cells. Finally, using a human colon cancer xenograft murine model, we found that the combined 5‐FU and 10058‐F4 treatment significantly decreased tumorigenicity in nude mice compared with 5‐FU or 10058‐F4 treatment alone. 10058‐F4 treatment decreased the ABCB5 expression level in the presence or absence of 5‐FU. In contrast, 5‐FU treatment alone increased the ABCB5 expression level. Taken together, these results suggest that c‐MYC confers resistance to 5‐FU through regulating ABCB5 expression in human colon cancer cells.