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      Retinoic acid and cancer treatment

      research-article
      , , ,
      Biomedicine
      China Medical University
      Retinoic acid, Cancer

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          Abstract

          Retinoic acid which belongs to the retinoid class of chemical compounds is an important metabolite of vitamin A in diets. It is currently understood that retinoic acid plays important roles in cell development and differentiation as well as cancer treatment. Lung, prostate, breast, ovarian, bladder, oral, and skin cancers have been demonstrated to be suppressed by retinoic acid. Our results also show that low doses and high doses of retinoic acid may respectively cause cell cycle arrest and apoptosis of cancer cells. Also, the common cell cycle inhibiting protein, p27, and the new cell cycle regulator, Cdk5, are involved in retinoic acid’s effects. These results provide new evidence indicating that the molecular mechanisms of/in retinoic acid may control cancer cells’ fates. Since high doses of retinoic acid may lead to cytotoxicity, it is probably best utilized as a potential supplement in one’s daily diet to prevent or suppress cancer progression. In this review, we have collected numerous references demonstrating the findings of retinoic acid in melanoma, hepatoma, lung cancer, breast cancer, and prostate cancer. We hope these observations will shed light on the future investigation of retinoic acid in cancer prevention and therapy.

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          Most cited references71

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          Retinoids, retinoic acid receptors, and cancer.

          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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            Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition.

            It is necessary to understand mechanisms by which differentiating agents influence tumor-initiating cancer stem cells. Toward this end, we investigated the cellular and molecular responses of glioblastoma stem-like cells (GBM-SCs) to all-trans retinoic acid (RA). GBM-SCs were grown as non-adherent neurospheres in growth factor supplemented serum-free medium. RA treatment rapidly induced morphology changes, induced growth arrest at G1/G0 to S transition, decreased cyclin D1 expression and increased p27 expression. Immunofluorescence and western blot analysis indicated that RA induced the expression of lineage-specific differentiation markers Tuj1 and GFAP and reduced the expression of neural stem cell markers such as CD133, Msi-1, nestin and Sox-2. RA treatment dramatically decreased neurosphere-forming capacity, inhibited the ability of neurospheres to form colonies in soft agar and inhibited their capacity to propagate subcutaneous and intracranial xenografts. Expression microarray analysis identified ∼350 genes that were altered within 48 h of RA treatment. Affected pathways included retinoid signaling and metabolism, cell-cycle regulation, lineage determination, cell adhesion, cell-matrix interaction and cytoskeleton remodeling. Notch signaling was the most prominent of these RA-responsive pathways. Notch pathway downregulation was confirmed based on the downregulation of HES and HEY family members. Constitutive activation of Notch signaling with the Notch intracellular domain rescued GBM neurospheres from the RA-induced differentiation and stem cell depletion. Our findings identify mechanisms by which RA targets GBM-derived stem-like tumor-initiating cells and novel targets applicable to differentiation therapies for glioblastoma.
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              Suppression of mammary carcinoma cell growth by retinoic acid: the cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling.

              The anticarcinogenic activities of retinoic acid (RA) are believed to be mediated by the nuclear RA receptor (RAR) and by the RA-binding protein cellular RA-binding protein-II (CRABP-II). In MCF-7 mammary carcinoma cells, growth inhibition by RA entails an early cell cycle arrest followed by induction of apoptosis. Here, we aimed to obtain insights into the initial cell cycle response. We show that a 3- to 5-h RA pulse is sufficient for inducing a robust growth arrest 2 to 4 days later, demonstrating inhibition of the G1-S transition by RA is triggered by immediate-early RAR targets and does not require the continuous presence of the hormone throughout the arrest program. Expression array analyses revealed that RA induces the expression of several genes involved in cell cycle regulation, including the p53-controlled antiproliferative gene B-cell translocation gene, member 2 (Btg2) and the BTG family member Tob1. We show that induction of Btg2 by RA does not require de novo protein synthesis and is augmented by overexpression of CRABP-II. Additionally, we identify a RA response element in the Btg2 promoter and show that the element binds retinoid X receptor/RAR heterodimers in vitro, is occupied by the heterodimers in cells, and can drive RA-induced activation of a reporter gene. Hence, Btg2 is a novel direct target for RA signaling. In concert with the reports that Btg2 inhibits cell cycle progression by down-regulating cyclin D1, induction of Btg2 by RA was accompanied by a marked decrease in cyclin D1 expression. The observations thus show that the antiproliferative activity of RA in MCF-7 cells is mediated, at least in part, by Btg2.
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                Author and article information

                Contributors
                hlin@dragon.nchu.edu.tw
                jonyin@gmail.com
                Journal
                Biomedicine (Taipei)
                Biomedicine (Taipei)
                Biomedicine
                China Medical University (Taichung )
                2211-8020
                2211-8039
                28 November 2014
                28 November 2014
                2014
                : 4
                : 22
                Affiliations
                [ ]Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taichung, Taiwan
                [ ]Department of Life Sciences, National Chung Hsing University, No. 250, Kuokuang Rd., Taichung 402, Taichung, Taiwan
                [ ]Department of Chest Medicine, Taichung Veterans General Hospital, No. 160, Taichung Harbor Rd., Sec. 3, Taichung 407, Taichung, Taiwan
                Article
                22
                10.7603/s40681-014-0022-1
                4265016
                25520935
                d3f489fc-bd3c-4bb6-ba3d-89402f1bc465
                © China Medical University 2014
                History
                : 15 October 2014
                : 5 November 2014
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2014

                retinoic acid,cancer
                retinoic acid, cancer

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