Interference of Frizzled 1 (FZD1) reverses multidrug resistance in breast cancer cells through the Wnt/β-catenin pathway

Zhang, Hui; Zhang, Xiaofang; Wu, Xiaojuan; Li, Weiwei; Su, Peng; Cheng, Hongxia; Xiang, Lei; Gao, Peng; Zhou, Guangjun

doi:10.1016/j.canlet.2012.03.039

Cited by 101 publications

(72 citation statements)

References 32 publications

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“…The paradoxical roles of RAR␥ in the regulation of ␤-catenin might depend on its particular cellular location. Additionally, the activation of Wnt/␤-catenin signaling contributes to multidrug resistance of tumor or endothelial cells through upregulation of P-gp (18,19,21). Indeed, we also found that RAR␥ upregulated P-gp expression through activation of the Wnt/␤-catenin pathway.…”

Section: Discussionmentioning

confidence: 60%

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Oncogenic Activity of Retinoic Acid Receptor γ Is Exhibited through Activation of the Akt/NF-κB and Wnt/β-Catenin Pathways in Cholangiocarcinoma

Huang

Luo

Rui

et al. 2013

Molecular and Cellular Biology

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c Aberrant expression and function of retinoic acid receptor ␥ (RAR␥) are often involved in the progression of several cancers. However, the role of RAR␥ in cholangiocarcinoma (CCA), chemoresistant bile duct carcinoma with a poor prognosis, remains unclear. In the present study, we found that RAR␥ was frequently overexpressed in human CCA specimens. Its overexpression was associated with poor differentiation, lymph node metastasis, high serum carbohydrate antigen 19-9 level, and poor prognosis of CCA. Downregulation of RAR␥ reduced CCA cell proliferation, migration, invasion, and colony formation ability in vitro and tumorigenic potential in nude mice. RAR␥ knockdown resulted in upregulation of cell cycle inhibitor P21, as well as downregulation of cyclin D1, proliferating cell nuclear antigen, and matrix metallopeptidase 9, in parallel with suppression of the Akt/ NF-B pathway. Furthermore, overexpression of RAR␥ contributed to the multidrug chemoresistance of CCA cells, at least in part due to upregulation of P glycoprotein via activation of the Wnt/␤-catenin pathway. Molecular mechanism studies revealed that RAR␥ interacted with ␤-catenin and led to ␤-catenin nuclear translocation. Taken together, our results suggested that RAR␥ plays an important role in the proliferation, metastasis, and chemoresistance of CCA through simultaneous activation of the Akt/NF-B and Wnt/␤-catenin pathways, serving as a potential molecular target for CCA treatment. C holangiocarcinoma (CCA) is the second most common primary hepatic malignancy, next to hepatocellular carcinoma (HCC) originating from bile duct epithelia (1). The incidence of this deadly neoplasm has increased rapidly in the past 3 decades. CCA is characterized by poor prognosis and a 5-year survival rate of less than 5% because of its remarkably high malignancy, early metastasis, and multidrug resistance (2). Thus, it is urgent to address the mechanisms underlying CCA proliferation, metastasis, and chemoresistance for the development of novel therapeutic strategies.Like other nuclear receptors, retinoic acid receptors (RARs) are transcription factors that are essential in embryonic development, maintenance of differentiated cellular phenotypes, metabolism, and cell death (3, 4). There are three RAR subtypes: ␣, ␤, and ␥. Among them, RAR␥ plays unique and uncharacterized roles in many different cell types and specific cell microenvironments. For example, RAR␥ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation (5). It also mediates the retinoic acid (RA)-induced growth arrest and differentiation of S91 murine melanoma cells (6). Overexpression of RAR␥ increases death of SH-SY5Y neuroblastoma cells in response to RA (7), suppresses the progression of nonhematopoietic-cell-intrinsic myeloproliferative syndromes (8), and inhibits the invasiveness of melanoma by RAR␥-inducible gene carbohydrate sulfotransferase 10 (9). RAR␥ also shows an antiproliferative property in mouse keratinocytes (10).One of the mechanisms that u...

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Section: Discussionmentioning

confidence: 60%

“…Cyclin D1, a target of the Wnt/␤-catenin pathway (18)(19)(20)(21), was downregulated in shRAR␥ cells (Fig. 2G).…”

Section: Clinical Significance and Overexpression Of Rar␥ In Ccamentioning

confidence: 99%

Oncogenic Activity of Retinoic Acid Receptor γ Is Exhibited through Activation of the Akt/NF-κB and Wnt/β-Catenin Pathways in Cholangiocarcinoma

Huang

Luo

Rui

et al. 2013

Molecular and Cellular Biology

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“…Furthermore, many signaling pathways have been associated with chemotherapy resistance, including the Wnt signaling pathway (36)(37)(38)(39)(40). Previous studies indicated that dysregulation of the Wnt/β-catenin signaling pathway is involved in pancreatic cancer chemoresistance (39).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer

Cui

Shen

et al. 2014

Oncology Reports

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Abstract. Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), a marker of adult stem cells and cancer stem cells, plays important roles in tumor progression. Furthermore, Lgr5 also contributes to chemoradiotherapy resistance. However, the function of Lgr5 in the prediction of preoperative chemotherapy efficacy has not been reported. We evaluated the potential of Lgr5 in predicting tumor response and overall survival in advanced gastric cancer treated with preoperative chemotherapy. The association between Lgr5 and chemotherapy resistance was also investigated in gastric cancer cell lines. Hematoxylin and eosin staining and immunohistochemical analysis of Lgr5 expression were performed in 68 cases of gastric cancer treated with preoperative chemotherapy. Lgr5 expression was specifically silenced in the AGS gastric cancer cell lines by RNA interference. Levels of Lgr5 mRNA and protein in cell lines were detected by quantitative reverse transcription-polymerase chain reaction or western blotting. Cell viability was evaluated by an MTT assay. Cell apoptosis was assessed by Annexin V-FITC/propidium iodide dual staining analysis. We found that Lgr5 expression was significantly associated with tumor regression grade after preoperative chemotherapy. The rate of positive Lgr5 expression was significantly higher in patients with poor tumor regression compared with those exhibiting tumor regression (P= 0.001). Lgr5-positive patients had a significantly shorter survival time than Lgr5-negative patients (P=0.001). Inhibition of Lgr5 expression with small interfering RNA increased the sensitivity of AGS gastric cancer cells to chemotherapy. Our findings suggest that Lgr5 expression may be implicated in the chemoresistance of gastric cancer cells and is a potential novel biomarker for predicting response to chemotherapy and prognosis in gastric cancer patients, and may also represent a potential new therapeutic target for cancer therapy.

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“…Recent studies have reported that altered WNT/β-catenin signaling can change the sensitivity of tumor cells to therapeutic drugs (21)(22)(23)(24), yet potential roles for β-catenin-independent WNT signaling in drug resistance are not well understood. In the present study, we found that WNT5A protein and transcript levels were dramatically increased in BRAFi-resistant cell lines and in patient tumors.…”

Section: Introductionmentioning

confidence: 99%

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

et al. 2014

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About half of all melanomas harbor a mutation that results in a constitutively active BRAF kinase mutant (BRAF V600E/K ) that can be selectively inhibited by targeted BRAF inhibitors (BRAFis). While patients treated with BRAFis initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. Here, we observed marked elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein were also elevated in BRAFiresistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction of endogenous WNT5A in melanoma decreased cell growth, increased apoptosis in response to BRAFi challenge, and decreased the activity of prosurvival AKT signaling. Conversely, overexpression of WNT5A promoted melanoma growth, tumorigenesis, and activation of AKT signaling. Similarly to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibited growth, sensitized melanoma cells to BRAFi, and reduced AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which promotes AKT signaling through FZD7 and RYK, leading to increased growth and therapeutic resistance. Furthermore, increased WNT5A expression in BRAFi-resistant melanomas correlates with a specific transcriptional signature, which identifies potential therapeutic targets to reduce clinical BRAFi resistance.

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Interference of Frizzled 1 (FZD1) reverses multidrug resistance in breast cancer cells through the Wnt/β-catenin pathway

Cited by 101 publications

References 32 publications

Oncogenic Activity of Retinoic Acid Receptor γ Is Exhibited through Activation of the Akt/NF-κB and Wnt/β-Catenin Pathways in Cholangiocarcinoma

Oncogenic Activity of Retinoic Acid Receptor γ Is Exhibited through Activation of the Akt/NF-κB and Wnt/β-Catenin Pathways in Cholangiocarcinoma

Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

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