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Lee MO, Han SY, Jiang S, Park JH, Kim SJDifferential effects of retinoic acid on growth and apoptosis in human colon cancer cell lines associated with the induction of retinoic acid receptor beta. Biochem Pharmacol 59: 485-496

Institute for Immunology and Immunological Diseases, Yonsei University, Sŏul, Seoul, South Korea
Biochemical Pharmacology (Impact Factor: 5.01). 04/2000; 59(5):485-96. DOI: 10.1016/S0006-2952(99)00355-X
Source: PubMed

ABSTRACT

Retinoids are well known as potential chemopreventive and chemotherapeutic agents against a variety of human cancers. Here, we report that retinoic acid (RA) induced differential growth inhibition in human colon cancer cell lines: while DLD-1, HT-29, and WiDr were relatively resistant, HCT-15 and Colo201 were relatively sensitive. All-trans-retinoic acid caused morphological and biochemical changes such as membrane shrinkage, chromatin condensation, and DNA cleavage, which are typical features of cells undergoing apoptosis in sensitive cell lines. Although retinoic acid receptor (RAR)alpha, beta, gamma and retinoid X receptor alpha were expressed in all cell lines examined, a significant induction of RARbeta by all-trans-RA was observed only in sensitive cell lines, suggesting important roles of RARbeta in RA sensitivity. When a vector containing the RARbeta gene was introduced into a relatively resistant cell line, DLD-1, the cells acquired RA sensitivity. Further, we found that the RARbeta transfectants of DLD-1 expressed an enhanced level of c-Myc and Bax proteins, which may result in the increased susceptibility of the cells to all-trans-RA-induced apoptosis. In summary, our data demonstrated that RA induced growth inhibition and apoptosis in human colon cancer cells and that the induction of RAR3 may mediate the retinoid action.

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    • "In HT-29 cells ATRA-induced growth inhibition is mediated by RARα [49], whereas, in Caco-2 cells it is mediated by RARβ [50]. However, other studies have reported that ATRA has no effect on growth inhibition in HT-29 cells [27]. In certain contexts, ATRA also has the ability to mediate apoptosis [35]. "
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    ABSTRACT: Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT1R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT2R) is lost. Further, our previous data indicate that patients with high CysLT1R and low CysLT2R expression have a poor prognosis. In this study, we examined whether the balance between CysLT1R and CysLT2R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA). To determine the effect of ATRA on CysLT2R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions. ATRA treatment induces CysLT2R mRNA and protein expression without affecting CysLT1R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor (RAR) dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C4 synthase, the enzyme responsible for the production of the ligand for CysLT2R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT2R-specific inhibitor. This study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway.
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    • "Although the precise mechanisms for causing RA resistance is not yet clear, several factors in RA signalling have been shown to play important roles, such as poor expression of CRABPII c The Authors Journal compilation c 2012 Biochemical Society (cellular RA-binding protein 2)[36]and loss of RARβ induction in response to RA[37]. Interestingly, both RARβ and CRABPII have been suggested as tumour suppressors that are key to the antitumour action of RA383940. Since the defects of gene induction of RARβ and CRABPII by ATRA may contribute to RA resistance[36,41,42], we next examined the effects of luffariellolide on the expression of these two genes. "
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    ABSTRACT: Retinoids display anti-tumour activity on various cancer cells and therefore have been used as important therapeutic agents. However, adverse side effects and RA (retinoic acid) resistance limit further development and clinical application of retinoid-based therapeutic agents. We report in the present paper the identification of a natural marine product that activates RARs (RA receptors) with a chemical structure distinct from retinoids by high-throughput compound library screening. Luffariellolide was uncovered as a novel RAR agonist by inducing co-activator binding to these receptors in vitro, further inhibiting cell growth and regulating RAR target genes in various cancer cells. Structural and molecular studies unravelled a unique binding mode of this natural ligand to RARs with an unexpected covalent modification on the RAR. Functional characterization further revealed that luffariellolide displays chemotherapeutic potentials for overcoming RA resistance in colon cancer cells, suggesting that luffariellolide may represent a unique template for designing novel non-retinoid compounds with advantages over current RA drugs.
    Full-text · Article · May 2012 · Biochemical Journal
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    • "One of the major causes of the failure or even discontinuation of cancer treatment is the development of pleiotropic drug resistance2930. Retinoids have long been investigated in preclinical models, and clinical data have already supported the potential of these compounds as anticancer preventive and therapeutic agents313233. In previous studies we described a potent antitumoral activity of the retinoid IIF, in comparison with RA, in different cancer cell lines21222324252627. "
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    ABSTRACT: Multidrug resistance (MDR) is one of the major causes of failure of tumoral chemotherapy and it is often present in colorectal cancer. Some retinoids may have antitumoral effects also in MDR cancer cell lines. We investigated the anticancer effect of the all-trans retinoic acid (RA) and the 6-OH-11-O-hydroxyphenantrene (IIF), a specific ligand of Retinoid X Receptor (RXR), on a colon carcinoma doxorubicin resistant cell line (LoVoMDR). IIF and RA treatment inhibited proliferation and vitality and induced apoptosis in a time and dose dependent manner. Interestingly, IIF was significantly more effective than RA and in particular, IIF increased Bax and decreased Bcl-2 protein expression, as well as it inducer caspase-9, caspase-3 and PARP-1 cleavage after 24 hours of exposure. Furthermore, we studied the effects of these retinoids on two plasma membrane proteins that are involved in the mechanism of drug-resistance: Multidrug Resistance Protein-1 (MRP-1) and P-glycoprotein (P-gp). Expression and activity of P-gp, but not of MRP-1, was decreased by retinoids. Matrix Metalloproteinase-9 (MMP9) involved in cell invasion and metastasis and Extracellular Matrix Metalloproteinase Inducer (EMMPRIN), a glycoprotein able to activate MMPs, were significantly reduced after IIF treatment. In conclusion we can suggest that IIF could be used to overcome MDR in human colon carcinoma and it may be a powerful tool in the development of cancer therapies.
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