Abstract
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.
Highlights
Colorectal cancer (CRC) is the third most prevalent malignancy and the fourth leading cause of cancer mortality worldwide [1]
Data acquired showed that DVL13 was over-expressed in HCT-8/VCR cells compared with HCT-8, and HCT-8/VCR cells were more resistant to vincristine than HCT-8 cells (IC50 9.49 μM vs 1.23 μM) (Figure 1A–1C), suggesting that DVL was involved in CRC resistance to vincristine
Our present study showed that DVL family members contributed to multidrug resistance (MDR) in CRC
Summary
Colorectal cancer (CRC) is the third most prevalent malignancy and the fourth leading cause of cancer mortality worldwide [1]. Surgery and chemotherapy are two major treatments for CRC. Systemic chemotherapy is often proposed as the firstline adjuvant treatment for patients with advanced CRC, aiming to palliate symptoms and prolong life [2]. Anticancer drugs such as vincristine, 5-fluorouracil and oxaliplatin are vital chemotherapy agents for CRC [3, 4]. The emergence of multidrug resistance (MDR) in CRC has greatly limited chemotherapeutic efficacy of the drugs, and results in therapy failure [5,6,7]. Overcoming MDR becomes a critical challenge in fighting against CRC
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