Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

Goranov, Bojidar; Hewson, Q D Campbell; Pearson, Andrew D.J.; Redfern, Christopher P.F.

doi:10.1038/sj.cdd.4401824

Cited by 13 publications

(11 citation statements)

References 18 publications

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“…RAR␥ acts as a tumor suppressor or oncogene in different cancers, depending on the cell-specific context (6)(7)(8)(9)(10)15). In the present study, we provided strong evidence that RAR␥ is a pivotal oncogene in CCA.…”

Section: Discussionsupporting

confidence: 60%

“…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).…”

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confidence: 99%

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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: Discussionsupporting

confidence: 60%

mentioning

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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“…The results from in vitro and in vivo studies showed that silencing RARg expression significantly enhanced colorectal cancer cell growth, migration, invasion, and metastasis, whereas ectopic expression of RARg did the opposite, suggesting that RARg functions as a novel tumor suppressor in colorectal cancer. Consistently, in neuroblastoma, RARg is believed to mediate the effect of RA on antiproliferative activity (11). Ablation of RARg in Ras-transformed keratinocytes induced tumorigenesis through resisting RA-mediated growth arrest and apoptosis (13).…”

Section: Discussionmentioning

confidence: 96%

RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway

Guo

Gan

et al. 2016

Cancer Research

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The Hippo-Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RARg as a regulator of the Hippo-Yap pathway in colorectal tumorigenesis and metastasis. RARg is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNM stage, and distant metastasis. Functional studies established that silencing of RARg drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo. Mechanistically, RARg controlled Hippo-Yap signaling to inhibit colorectal cancer development, acting to promote phosphorylation and binding of Lats1 to its transcriptional coactivator Yap and thereby inactivating Yap target gene expression. In clinical specimens, RARg expression correlated with overall survival outcomes and expression of critical Hippo-Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RARg as tumor suppressor in colorectal cancer that acts by restricting oncogenic signaling by the Hippo-Yap pathway, with potential implications for new approaches to colorectal cancer therapy.Cancer Res; 76(13); 3813-25. Ó2016 AACR.

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“…An alternative approach to overcoming RA resistance caused by RARβ 2 silencing is to use nonclassical retinoids that have both receptordependent and receptor-independent activities (127, 140). Recent preclinical studies show that, in addition to RARβ 2 , RARγ (141,142) and RXRs (143,144) can function as tumor suppressors in various types of tumor cells; these findings indicate that specific agonists for RARγ and RXRs (144,145) have potential for the treatment of human cancers.…”

Section: Pharmacological Uses Of Retinoids In Cancer Treatment and Thmentioning

confidence: 97%

Retinoids, Retinoic Acid Receptors, and Cancer

Tang

Gudas

2011

Annu. Rev. Pathol. Mech. Dis.

515

487

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Retinoids (i.e., vitamin A, all-trans retinoic acid, and related signaling molecules) induce the differentiation of various types of stem cells. Nuclear retinoic acid receptors mediate most but not all of the effects of retinoids. Retinoid signaling is often compromised early in carcinogenesis, which suggests that a reduction in retinoid signaling may be required for tumor development. Retinoids interact with other signaling pathways, including estrogen signaling in breast cancer. Retinoids are used to treat cancer, in part because of their ability to induce differentiation and arrest proliferation. Delivery of retinoids to patients is challenging because of the rapid metabolism of some retinoids and because epigenetic changes can render cells retinoid resistant. Successful cancer therapy with retinoids is likely to require combination therapy with drugs that regulate the epigenome, such as DNA methyltransferase and histone deacetylase inhibitors, as well as classical chemotherapeutic agents. Thus, retinoid research benefits both cancer prevention and cancer treatment.

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Overexpression of RARγ increases death of SH-SY5Y neuroblastoma cells in response to retinoic acid but not fenretinide

Cited by 13 publications

References 18 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

RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway

Retinoids, Retinoic Acid Receptors, and Cancer

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