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...

Glioma is the most common type of malignant brain tumor. Due to its highly aggressive and metastatic features, glioma is associated with poor prognosis and a lack of effective treatments. Eriodictyol, a natural flavonoid compound, has been reported to possess antiinflammatory and antioxidant effects. However, the anti-tumor effects of eriodictyol and the underlying mechanisms have rarely been reported. In this study, we found that eriodictyol has anti-tumor activity in lung, colon, breast, pancreas, and liver cancer, and most significantly in glioma cell lines. Eriodictyol dose-and time-dependently suppresses cell proliferation, migration, and invasion in U87MG and CHG-5 glioma cells. In addition, eriodictyol induces apoptosis in U87MG and CHG-5 cells, as evaluated by flow cytometry, immunofluorescence, and Western blot. Furthermore, eriodictyol downregulates the phosphoinositide 3-kinase (PI3K)/Akt/NF-kB signaling pathway in a concentrationdependent manner. Moreover, the effects of eriodictyol on the apoptosis of glioma cells are enhanced by LY294002 (a PI3K inhibitor) and reversed by 740 Y-P (a PI3K agonist). In a mouse xenograft model, eriodictyol not only dramatically suppressed tumor growth but also induced apoptosis in tumor cells. In summary, our data illustrate that eriodictyol effectively inhibits proliferation and metastasis and induces apoptosis of glioma cell lines, which might be a result of the blockade of the PI3K/Akt/NF-kB signaling pathway.

Retinoic acid receptor γ (RARγ), a unique member of the nuclear receptor superfamily, plays an important role in the progression of several cancers such as hepatocellular carcinoma, esophageal cancer, and cholangiocarcinoma. However, little is known about the regulatory mechanism of the RARγ expression in colorectal cancer (CRC) progression. In the present study, we found that RARγ was frequently overexpressed in human CRC specimens and CRC cell lines, and it mainly resided in the cytoplasm in CRC specimens. Tissue microarrays showed that RARγ indicated vital clinical significance in CRC. RARγ knockdown neither affected CRC cell proliferation nor blocked the cell cycle of CRC cells. However, RARγ knockdown increased the sensitivity of CRC cells to chemotherapeutics through downregulation of multi-drug resistance 1(MDR1). Further studies suggested that RARγ knockdown resulted in downregulation of MDR1, in parallel with suppression of the Wnt/β-catenin pathway. Moreover, a significantly positive association between RARγ and MDR1 was demonstrated in CRC tissue microarrays. Collectively, these results suggested that overexpression of RARγ contributed to the multidrug chemoresistance of CRC cells, at least in part due to upregulation of MDR1 via activation of the Wnt/β-catenin pathway, indicating that RARγ might serve as a potential therapeutic target for chemoresistant CRC patients.

β-escin was a potent reverser of P-gp-dependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3β/β-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.

Retinoid X receptor α (RXRα) plays important roles in the malignancy of several cancers such as human prostate tumor, breast cancer, and thyroid tumor. However, its exact functions and molecular mechanisms in cholangiocarcinoma (CCA), a chemoresistant carcinoma with poor prognosis, remain unclear. In this study we found that RXRα was frequently overexpressed in human CCA tissues and CCA cell lines. Downregulation of RXRα led to decreased expression of mitosis‐promoting factors including cyclin D1and cyclin E, and the proliferating cell nuclear antigen, as well as increased expression of cell cycle inhibitor p21, resulting in inhibition of CCA cell proliferation. Furthermore, RXRα knockdown attenuated the expression of cyclin D1 through suppression of Wnt/β‐catenin signaling. Retinoid X receptor α upregulated proliferating cell nuclear antigen expression through nuclear factor‐κB (NF‐κB) pathways, paralleled with downregulation of p21. Thus, the Wnt/β‐catenin and NF‐κB pathways account for the inhibition of CCA cell growth induced by RXRα downregulation. Retinoid X receptor α plays an important role in proliferation of CCA through simultaneous activation of Wnt/β‐catenin and NF‐κB pathways, indicating that RXRα might serve as a potential molecular target for CCA treatment.