Twist1 confers multidrug resistance in colon cancer through upregulation of ATP-binding cassette transporters
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Yan-Rong Liu1,*, Lan Liang3,*, Jian Min Zhao4,*, Yang Zhang5,*, Min Zhang1,2, Wei-Long Zhong1,2, Qiang Zhang1,2, Jun-Jie Wei1,2, Meng Li1,2, Jie Yuan1,2, Shuang Chen1, Shu-Min Zong1,2, Hui-Juan Liu1, Jing Meng1,2, Yuan Qin1,2, Bo Sun1, Lan Yang1, Hong-Gang Zhou1,2, Tao Sun1,2 and Cheng Yang1,2
1Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
2State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China
3Tianjin GoalGen Biotechnology Co., Ltd., Tianjin, China
4Pathology Department, Shun Yi District Hospital, Beijing, China
5Department of Anesthesiology, Tianjin 4th Center Hospital, Tianjin, China
*These authors have contributed equally to this work
Cheng Yang, email: firstname.lastname@example.org
Tao Sun, email: email@example.com
Keywords: Twist1, multidrug resistance, colon cancer, ABCB1, ABCC1
Received: December 29, 2016 Accepted: March 30, 2017 Published: May 02, 2017
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.
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