Inhibition of Transient Receptor Potential Channel 5 Reverses 5-Fluorouracil Resistance in Human Colorectal Cancer Cells |
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| Authors: | Teng Wang Zhen Chen Yifei Zhu Qiongxi Pan Yanjun Liu Xiaowei Qi Linfang Jin Jian Jin Xin Ma Dong Hua |
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| Affiliation: | From the Departments of ‡Medical Oncology and ;¶Pathology, Affiliated Hospital of Jiangnan University and Fourth People''s Hospital of Wuxi, Wuxi, Jiangsu 214062, China and ;the §School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China |
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| 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. |
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| Keywords: | ABC Transporter Beta-Catenin (B-catenin) Chemoresistance Colorectal Cancer Transient Receptor Potential Channels (TRP Channels) |
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