Repressing PDCD4 activates JNK/ABCG2 pathway to induce chemoresistance to fluorouracil in colorectal cancer cells
Lanlin Hu, Yutong Liang, Kelv Wu, Caixia Wang, Tao Zhang, Rui Peng, Fangdong Zou
Abstract
BACKGROUND: Colorectal cancer (CRC) is the third major cause of cancer-related death worldwide, and fluorouracil (5-FU) is widely used in the treatment of CRC. However, acquired resistance to 5-FU has become an obstacle in the effective treatment of CRC. Adenosine triphosphate (ATP)-binding cassette sub-family G member 2 (ABCG2) has been found highly expressed in CRC patients with poor responsiveness to folinic acid/5-FU/irinotecan. However, the mechanisms of 5-FU resistance regulated by ABCG2 in CRC cells remain to be comprehensively understood. We aimed to explore the upstream mechanisms of ABCG2 involved in the regulation of chemoresistance in CRC cells. METHODS: We investigated the potential mechanisms of 5-FU resistance in HCT116, RKO, RKO microRNA-21 (miR-21) knockout, and acquired 5-FU-resistant HCT116 (HCT116/FUR) cells. The biochemical and biological analyses were conducted using semiquantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, transfections, and rescue experiments, along with cell proliferation, viability, and colony formation assays. In order to investigate the efficacy of inhibiting the c-Jun NH2 terminal kinase (JNK) pathway to overcome 5-FU resistance, HCT116 and 5-FU-resistant HCT116 cells were inoculated into BALB/c-nu/nu mice to establish the cell-derived xenograft model. RESULTS: . CONCLUSIONS: .