Dishevelled1-3 contribute to multidrug resistance in colorectal cancer via activating Wnt/β-catenin signaling
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Kun Zhang1,*, Minhui Li2,*, Houyi Huang1,*, Linpeng Li1,*, Jie Yang1, Li Feng1, Junjie Gou1, Mengju Jiang1, Liaotian Peng1, Linyi Chen1, Ting Li1, Ping Yang2, Yuhan Yang1, Yuanyuan Wang1, Quekun Peng1, Xiaozhen Dai1 and Tao Zhang1
1School of Biomedical Sciences, Chengdu Medical College, Chengdu, 610041, Sichuan, China
2School of Basic Medical Sciences, Chengdu Medical College, Chengdu, 610041, Sichuan, China
*These authors contributed equally to this work
Kun Zhang, email: [email protected]
Tao Zhang, email: [email protected]
Xiaozhen Dai, email: [email protected]
Keywords: multidrug resistance; colorectal cancer; drug sensitivity; dishevelled; Wnt/β-catenin
Received: October 02, 2017 Accepted: November 13, 2017 Published: December 14, 2017
Multidrug resistance is a great obstacle in successful chemotherapy of colorectal cancer. However, the molecular mechanism underlying multidrug resistance is not fully understood. Dishevelled, a pivot in Wnt signaling, has been linked to cancer progression, while its role in chemoresistance remains unclear. Here, we found that Dishevelled1-3 was over-expressed in multidrug-resistant colorectal cancer cells (HCT-8/VCR) compared to their parental cells. Silencing Dishevelled1-3 resensitized HCT-8/VCR cells to multiple drugs including vincristine, 5-fluorouracil and oxaliplatin. Moreover, Dishevelled1-3 increased the protein levels of multidrug resistance protein 1 (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), Survivin and Bcl-2 which are correlated with multidrug resistance. shβ-catenin abolished Dishevelled-mediated these protein expressions. Unexpectedly, none of Dishevelled1-3 controlled β-catenin accumulation and nuclear translocation. Furthermore, the nuclear translocations of Dishevelled1-3 were promoted in HCT-8/VCR cells compared to HCT-8. Dishevelled1-3 bound to β-catenin in nucleus, and promoted nuclear complex formation and transcription activity of β-catenin/TCF. Taken together, Dishevelled1-3 contributed to multidrug resistance in colorectal cancer via activating Wnt/β-catenin signaling and inducing the expressions of P-gp, MRP2, BCRP, Survivin and Bcl-2, independently of β-catenin accumulation and nuclear translocation. Silencing Dishevelled1-3 resensitized multidrug-resistant colorectal cancer cells, providing a novel therapeutic target for successful chemotherapy of colorectal cancer.
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