Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters

// Yan-Rong Liu 1, * , Lan Liang 3, * , Jian Min Zhao 4, * , Yang Zhang 5, * , Min Zhang 1, 2 , Wei-Long Zhong 1, 2 , Qiang Zhang 1, 2 , Jun-Jie Wei 1, 2 , Meng Li 1, 2 , Jie Yuan 1, 2 , Shuang Chen 1 , Shu-Min Zong 1, 2 , Hui-Juan Liu 1 , Jing Meng 1, 2 , Yuan Qin 1, 2 , Bo Sun 1 , Lan Yang 1 , Hong-Gang Zhou 1, 2 , Tao Sun 1, 2 and Cheng Yang 1, 2 1 Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China 2 State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China 3 Tianjin GoalGen Biotechnology Co., Ltd., Tianjin, China 4 Pathology Department, Shun Yi District Hospital, Beijing, China 5 Department of Anesthesiology, Tianjin 4th Center Hospital, Tianjin, China * These authors have contributed equally to this work Correspondence to: Cheng Yang, email: cheng.yang@nankai.edu.cn Tao Sun, email: sunrockmia@hotmail.com Keywords: Twist1, multidrug resistance, colon cancer, ABCB1, ABCC1 Received: December 29, 2016 Accepted: March 30, 2017 Published: May 02, 2017 ABSTRACT Multidrug resistance is a major problem in colon cancer treatment. However, its molecular mechanisms remain unclear. Recently, the epithelial-mesenchymal transition (EMT) in anticancer drug resistance has attracted increasing attention. This study investigated whether vincristine treatment induces EMT and promotes multidrug resistance in colon cancer. The result showed that vincristine treatment increases the expression of several ATP-binding cassette transporters in invasive human colon adenocarcinoma cell line (HCT-8). Vincristine-resistant HCT-8 cells (HCT-8/V) acquire a mesenchymal phenotype, and thus its migratory and invasive ability are increased both in vitro and in vivo . The master transcriptional factors of EMT, especially Twist1, were significantly increased in the HCT-8/V cell line. Moreover, the ectopic expression of Twist1 increased the chemoresistance of HCT-8 cells to vincristine and increased the expression levels and promoter activities of ABCB1 and ABCC1. Furthermore, Twist1 silencing reverses the EMT phenotype, enhances the chemosensitivity of HCT-8/ V cells to anticancer agents in vitro and in vivo , and downregulates the expression of ABCB1 and ABCC1. Twist1-mediated promotion of ABCB1 and ABCC1 expression levels plays an important role in the drug resistance of colon cancer cells.