FOXM1 evokes 5-fluorouracil resistance in colorectal cancer depending on ABCC10

Abstract

// Tao Xie 1, * , Jian Geng 1, * , Ye Wang 1 , Liya Wang 2 , Mengxi Huang 2 , Jing Chen 2 , Kai Zhang 2 , Lijun Xue 2 , Xiaobei Liu 2 , Xiaobei Mao 2 , Yanan Chen 2 , Qian Wang 2 , Tingting Dai 2 , Lili Ren 2 , Hongju Yu 2 , Rui Wang 2 , Longbang Chen 2 , Cheng Chen 1, 2 , Xiaoyuan Chu 1, 2 1 Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China 2 Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China * These authors have contributed equally to this work Correspondence to: Xiaoyuan Chu, email: chuxiaoyuan000@163.com Cheng Chen, email: chencheng1289@126.com Keywords: colorectal cancer, FOXM1, 5-FU, chemoresistance Received: September 07, 2016     Accepted: December 07, 2016     Published: December 29, 2016 ABSTRACT 5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, frequently occurred 5-FU resistance poses a great challenge in the clinic. Elucidating the underlying mechanisms and developing effective strategies against 5-FU resistance are highly desired. Here we identified the upregulation of FOXM1 in 5-FU nonresponsive CRC patients by gene expression profile analysis and 5-FU-resistant CRC cells by qRT-PCR assay. Silencing of FOXM1 promoted the sensitivity of CRC cells to 5-FU by enhancing cell apoptosis, while overexpression of FOXM1 conferred CRC cells with 5-FU resistance both in vitro and in vivo . Furthermore, we showed that genetic and pharmacological inhibition of FOXM1 resensitized resistant CRC cells to 5-FU treatment. Mechanistically, FOXM1 promoted the transcription of ABCC10 by directly binding to its promoter region. Notably, treatment with ABCC10 inhibitor reversed FOXM1-induced resistance to 5-FU in vivo . Clinical investigation revealed that the levels of FOXM1 and ABCC10 were positively correlated in CRC tissues. Therefore, FOXM1 promotes 5-FU resistance by upregulating ABCC10, suggesting that FOXM1/ABCC10 axis may serve as a potential therapeutic target for 5-FU resistance in CRC patients.