title: Inhibition of transient receptor potential channel 5 reverses 5-Fluorouracil resistance in human colorectal cancer cells.
abstract: 5-Fluorouracil (5-Fu) is commonly used in the chemotherapy of colorectal cancer (CRC), but resistance to 5-Fu occurs in most cases, allowing cancer progression. Suppressing ABCB1 (ATP-binding cassette, subfamily B, member 1), which is a pump overproduced in cancer cells to export cytotoxic drugs, is an attractive strategy to overcome drug resistance. In the present study, transient receptor potential channel TrpC5 was found to be overproduced at the mRNA and protein levels together with ABCB1 in 5-Fu-resistant human CRC HCT-8 (HCT-8/5-Fu) and LoVo (LoVo/5-Fu) cells. More nuclear-stabilized β-catenin accumulation was found in HCT-8/5-Fu and LoVo/5-Fu cells than in HCT-8 and LoVo cells. Suppressing TrpC5 expression with TrpC5-specific siRNA inhibited the canonical Wnt/β-catenin signal pathway, reduced the induction of ABCB1, weakened the ABCB1 efflux pump, and caused a remarkable reversal of 5-Fu resistance in HCT-8/5-Fu and LoVo/5-Fu cells. On the contrary, enforcing TrpC5 expression resulted in an activated Wnt/β-catenin signal pathway and up-regulation of ABCB1. Taken together, we demonstrated an essential role of TrpC5 in ABCB1 induction and drug resistance in human CRC cells via promoting nuclear β-catenin accumulation.
authors.affiliation: From the Departments of Medical Oncology and.
authors.forename: Teng
authors.initials: T
authors.lastname: Wang
authors.affiliation: the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Qiongxi
authors.initials: Q
authors.lastname: Pan
authors.affiliation: the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Pathology, Affiliated Hospital of Jiangnan University and Fourth People's Hospital of Wuxi, Wuxi, Jiangsu 214062, China and.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Qi
authors.affiliation: Pathology, Affiliated Hospital of Jiangnan University and Fourth People's Hospital of Wuxi, Wuxi, Jiangsu 214062, China and.
authors.forename: Linfang
authors.initials: L
authors.lastname: Jin
authors.affiliation: the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: the School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China maxin@jiangnan.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.affiliation: From the Departments of Medical Oncology and huadong@csco.org.cn.
authors.forename: Dong
authors.initials: D
authors.lastname: Hua
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels; C491780:TRPC5 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D005472:Fluorouracil
keywords: ABC Transporter; Beta-Catenin (B-catenin); Chemoresistance; Colorectal Cancer; Transient Receptor Potential Channels (TRP Channels)