Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:017982 (all-trans)
 8,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported the cloning of full-length cDNAs corresponding to mRNAs of three GST-pi genes, hGSTP1*A, hGSTP1*B and hGSTP1*C, as well as, the isolation of the full-length hGSTP1*C, of the human glutathione S-transferase-pi (GST-pi) gene that is characterized by a A-->G transition at +1404 in exon 5 and a C-->T transition at +2294 in exon 6. Although the promoter of the isolated gene was identical to that of the previously described GST-pi gene isolated from the MCF 7 and the HPB-ALL cell lines, both of which were hGSTP1*A, a number of structural differences were observed, including, nucleotide transitions, transversions, deletions and insertions, some of which created new restriction enzyme cleavage sites. A guanine insertion in the insulin response element, IRE, in intron 1 created an additional site for 5'-cytosine methylation. Seven repeat retinoic acid response element (RARE) consensus half sites, A(G)GG(T)TC(G)A at +1521 to +1644 were identified in the cloned hGSTP1*C. Five of the RARE half-sites had the minimal spacer nucleotide requirement for functionality and DNA mobility shift analysis with different pairs of the RARE half-sites and supershift studies using antibodies against RAR-beta showed significant binding of nuclear protein complexes from RA-treated cells to these RAREs. GST-pi gene expression was increased significantly in cells transfected with the GST-pi gene and treated with all-trans RA. These results contrast with those in a previous report in which RA was shown to suppress the GST-pi promoter, and indicate a complex mechanism of RA-mediated GST-pi gene regulation in tumor cells.
 ...
PMID:Structure of the human allelic glutathione S-transferase-pi gene variant, hGSTP1 C, cloned from a glioblastoma multiforme cell line. 967 46

The molecular signaling events involved in the inhibition of breast cancer cell growth by retinoic acid and interferon-alpha were investigated. All-trans-retinoic acid and interferon-alpha acted synergistically to inhibit growth of both the estrogen receptor-positive breast cancer cell line MCF-7 and the estrogen receptor-negative line BT-20. In MCF-7 cells, all-trans-retinoic acid potentiated the effects of interferon-alpha by up-regulating the expression of the RNA-dependent protein kinase (PKR). Consequently, the synergism between all-trans-retinoic acid and interferon-alpha down-regulated the expression of c-Myc, but not its functional partner, Max. Transfection of MCF-7 cells with a dominant-negative mutant of PKR relieved c-Myc down-regulation and cell growth inhibition, indicating that PKR is directly involved in c-Myc down-regulation and that c-Myc down-regulation is responsible for the inhibition of cell growth. Corresponding with c-Myc down-regulation, c-Myc.Max heterodimers bound to their consensus DNA sequence were undetectable in cells treated with all-trans-retinoic acid and interferon-alpha, indicating diminished c-Myc functionality. When c-Myc was overexpressed ectopically via a c-Myc expression vector, MCF-7 cells became resistant to growth inhibition by all-trans-retinoic acid plus interferon-alpha. These experiments define the following pathway as a major pathway in the synergistic growth inhibition of MCF-7 cells by all-trans-retinoic acid plus interferon-alpha: all-trans-retinoic acid + interferon-alpha --> upward arrow double-stranded RNA-dependent protein kinase --> downward arrow c-Myc --> cell growth inhibition.
 ...
PMID:c-Myc is a major mediator of the synergistic growth inhibitory effects of retinoic acid and interferon in breast cancer cells. 980 32

Solid tumors are relatively resistant to growth inhibition by IFNs. To enhance sensitivity, we assessed combinations of IFNs with all-trans-retinoic acid (RA). Antiproliferative studies in vitro suggested that the growth of three human breast carcinomas (MCF-7, MDA-MB-231, and MDA-MB-468), an ovarian carcinoma (NIH-OVCAR-3), and a malignant melanoma (SK-MEL-1) was inhibited to a greater degree by combination treatment with human IFN-beta and RA compared to single agents. Some of these cell lines were resistant to 10-100 IU/ml human IFN-alpha2b or IFN-beta or to 0.1-1.0 microM RA. Growth was inhibited significantly by combinations of IFNs and RA in all cell lines tested, and in some cases, cytotoxicity was observed. Sequential treatment of MCF-7 cells with RA followed by IFN-beta was more effective at inhibiting growth than treatment with IFN-beta followed by RA, suggesting that RA modulated the anticellular response of IFN-beta rather than the converse. In nude mice, the growth of MCF-7 and NIH-OVCAR-3 tumors was suppressed completely when combination treatment was started 2 days after tumor inoculation. Established, 6-week-old NIH-OVCAR-3 tumors underwent regression when treated with the combination of IFN-beta and RA but not with single-agent therapy. Together with our recent studies that demonstrated enhancement of IFN-stimulated gene expression by RA pretreatment in IFN-resistant cells, these data suggest that combination treatment with RA and IFNs may increase IFN-stimulated gene expression in IFN-resistant tumors, leading to augmented antitumor effects.
 ...
PMID:Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. 981 68

Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans- and 9-cis-retinoic acid, as well as the retinoic acid receptor gamma (RAR-gamma) selective agonists CD2325 and CD437 (1 microM), were able to down-regulate prolactin receptor. After 1 h, a significant reduction was detectable and maximal effect was achieved after 24 h of treatment. Pretreatment with retinoic acid also reduced the prolactin-/prolactin receptor-dependent signal transduction and activation of transcription 5 (STAT-5) activation in T47D cells. Cycloheximide failed to abrogate the retinoic acid-induced decline in prolactin receptor mRNA levels, indicating that this effect was not dependent upon continuing protein synthesis. Similarly, no change in the stability of prolactin receptor mRNA was observed during 12 h of retinoic acid treatment. In conclusion, our results demonstrate that retinoids are able to inhibit the expression of prolactin receptor message, which encodes an important growth factor receptor in breast cancer cells. This action could be responsible for the anti-tumour effects of retinoids.
 ...
PMID:Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro. 988 58

Neither retinoic acid receptor-beta (RARbeta) nor insulin-like growth factor-binding protein-3 (IGFBP-3) is expressed in breast cancer cell line MCF-7. The expression of both proteins can be induced in response to all-trans-retinoic acid (atRA). By using an RARalpha-selective antagonist (Ro 41-5253), we demonstrated that RARbeta expression was induced by atRA through an RARalpha-dependent signaling pathway and that RARbeta induction was correlated with IGFBP-3 induction. However, MCF-7 cells transfected with sense RARbeta cDNA expressed IGFBP-3 even in the presence of the RARalpha-selective antagonist Ro 41-5253. On the other hand, antisense RARbeta cDNA transfection of MCF-7 cells blocked atRA-induced IGFBP-3 expression, indicating that RARbeta is directly involved in the mediation of IGFBP-3 induction by atRA. Induction of IGFBP-3 expression by atRA occurs at the transcriptional level, as measured by nuclear run-on assays. Finally, we showed that atRA-induced IGFBP-3 is functionally active in modulating the growth-promoting effect of IGF-I. These experiments indicate that RARalpha and RARbeta, both individually and together, are important in mammary gland homeostasis and breast cancer development. By linking IGFBP-3 to RARbeta, our experiments define the signal intersection between the retinoid and IGF systems in cell growth regulation and explain why loss of RARbeta might be critical in breast cancer carcinogenesis/progression.
 ...
PMID:Signal relay by retinoic acid receptors alpha and beta in the retinoic acid-induced expression of insulin-like growth factor-binding protein-3 in breast cancer cells. 1036 50

In advanced or recurrent malignant diseases, retinoic acid (RA) is not effective, even at doses that are toxic to the host. In late stages of breast cancer, patients do not respond to RA because the expression of RA receptor beta (RARbeta) is lost. In the present study, the intracellular mechanism(s) of synergistic effects of RA and a site-selective cyclic AMP (cAMP) analogue, 8-chloro-adenosine 3',5'-cyclic monophosphate (8-Cl-cAMP), on growth inhibition and apoptosis in breast cancer cells was examined. Our data demonstrated that hormone-dependent MCF-7 cells, but not hormone-independent MDA-MB-231 cells, are sensitive to RA-induced growth inhibition and apoptosis. Introduction of the RARbeta gene into MDA-MB-231 cells resulted in a gain of RA sensitivity. 8-Cl-cAMP acted synergistically with all-trans-RA in inducing and activating RARbeta gene expression that correlates with the reduction in mitochondrial membrane potential, redistribution of cytochrome c, activation of caspases, cleavage of poly(ADP-ribose) polymerase and DNA-dependent protein kinase (catalytic subunit), and induction of apoptosis. Mutations in the cAMP response element-related motif within the RARbeta promoter resulted in loss of synergy in RARbeta transcription. In addition, inhibition of RARbeta expression by an antisense construct also blocked the antitumor effects of RA + 8-Cl-cAMP. Thus, RARbeta can mediate RA and/or cAMP action in breast cancer cells by promoting apoptosis. Therefore, loss of RARbeta expression may contribute to the tumorigenicity of human mammary epithelial cells. These findings suggest that RA and 8-Cl-cAMP act in a synergistic fashion and may have potential for combination biotherapy for the treatment of malignant diseases.
 ...
PMID:Synergistic effects of retinoic acid and 8-chloro-adenosine 3',5'-cyclic monophosphate on the regulation of retinoic acid receptor beta and apoptosis: involvement of mitochondria. 1043 97

We showed previously that the selenium-dependent glutathione peroxidase, GPX-GI, encoded by the Gpx2 gene, is highly expressed in the epithelium of the gastrointestinal (GI) tract and sporadically in breast tissue. To investigate whether Gpx2 gene expression is epithelium specific, we used in situ hybridization to show that Gpx2 mRNA is highly expressed in the crypt epithelium of human intestine. We also used Northern analysis to study human breast cells and found Gpx2 mRNA in human mammary epithelial cell lines as well as freshly isolated normal breast epithelial cells. Because we identified three putative retinoic acid response elements (RARE) in the Gpx2 gene, we examined the regulation of the Gpx2 gene expression by all-trans retinoic acid (RA) in RA-sensitive MCF-7 cells and RA-resistant HT29 cells. Without RA, MCF-7 cells had very low levels of Gpx2 mRNA and a low level of glutathione peroxidase (GPX) activity (17 mU/mg protein), whereas HT29 cells had a high level of Gpx2 mRNA and GPX activity (200 mU/mg protein). RA treatment increased Gpx2 mRNA level 3- to 11-fold and resulted in a fourfold increase of GPX activity (80 mU/mg protein) in MCF-7 cells. Neither Gpx2 mRNA level nor GPX activity was increased in HT29 cells. These results show that the Gpx2 gene is expressed in both breast and intestinal epithelium cells, and suggest that its expression can be highly regulated by retinoic acid, a known differentiation agent.
 ...
PMID:Retinoic acid induces Gpx2 gene expression in MCF-7 human breast cancer cells. 1049 57

Retinoic acid receptor-beta (RAR beta) and signal transducer and activator of transcription 1 (STAT1) are important mediators of the antiproliferative and apoptotic actions of retinoids and cytokines/growth factors, respectively. Expression of both RAR beta and STAT1 is lost in most breast cancer cell lines but it can be induced by retinoids in estrogen receptor-positive cells. We investigated a possible functional connection between these two mediators and present evidence supporting RAR beta as a tumor suppressor. First, by using different receptor-selective retinoids, we demonstrated that RAR beta induction in MCF-7 cells by all-trans-retinoic acid (atRA) was associated with the activation of STAT1 gene transcription. The direct involvement of RAR beta in atRA-induced STAT1 gene activation was further demonstrated by showing that transfection with an anti-sense RAR beta construct blocked atRA-induced STAT1 expression in MCF-7 cells whereas introduction of a sense-RAR beta construct resulted in STAT1 induction by atRA in MDA-MB 231 cells. In addition, we showed that STAT1 was phosphorylated/activated under atRA treatment of MCF-7 cells; this process required the involvement of RAR beta and protein synthesis. STAT1 phosphorylation/activation was accompanied by increased tyrosine kinase activity that was not due to the activation of JAK1, JAK2 or Tyk 2, suggesting the possible involvement of an unidentified tyrosine kinase.
 ...
PMID:The induction and activation of STAT1 by all-trans-retinoic acid are mediated by RAR beta signaling pathways in breast cancer cells. 1059 80

The organic arsenical known as melarsoprol (Mel-B) is used to treat African trypanosomiasis. Recently, another arsenical, As2O3 was shown to be effective in treatment of acute promyelocytic leukaemia. We have investigated the anti-tumour activities of Mel-B either with or without all-trans-retinoic acid (ATRA) using the MCF-7 human breast cancer cells, as well as the PC-3 and DU 145 human prostate cancer cells both in vitro and in vivo. The antiproliferative effects of Mel-B and/or ATRA against breast and prostate cancer were tested in vitro using clonogenic assays and in vivo in triple immunodeficient mice. Furthermore, the mechanism of action of these compounds was studied by examining the cell cycle, levels of bcl-2, apoptosis and antiproliferative potency using a pulse-exposure assay. Clonogenic assays showed that the cancer cell lines were sensitive to the inhibitory effect of Mel-B (effective dose that inhibited 50% clonal growth [ED50]: 7 x 10(-9) M for MCF-7, 2 x 10(-7) M for PC-3, 3 x 10(-7) M for DU145 cells. Remarkably, the combination of Mel-B and ATRA had an enhanced antiproliferative activity against all three cancer cell lines. Furthermore, the combination of Mel-B and ATRA induced a high level of apoptosis in all three cell lines. Treatment of PC-3 and MCF-7 tumours growing in triple immunodeficient mice with Mel-B and ATRA either alone or in combination markedly retarded tumour size and weight of the tumours without major side-effects. In conclusion, our results suggest that either Mel-B alone or with ATRA may be a useful, novel therapy for breast and prostate cancers.
 ...
PMID:Novel therapeutic approach: organic arsenical melarsoprol) alone or with all-trans-retinoic acid markedly inhibit growth of human breast and prostate cancer cells in vitro and in vivo. 1064 4

Cultured cells grown as spheroids provide an in vitro model that is closer to an in vivo tumour than conventional monolayer techniques. Previous work from our laboratory has demonstrated that spheroids formed from multidrug-resistant MCF-7 cells exhibit invasive characteristics which were not present in their sensitive counterparts. The treatment of these spheroids by all-trans-retinoic acid (ATRA), a potent inducer of in vitro and in vivo differentiation, decreases their proteolytic activity and ability to invade Matrigel-coated filters. The efficiency of ATRA is enhanced by its incorporation into low-density lipoprotein (LDL) (LDL-ATRA). Indeed, invasion through a reconstituted basement membrane was reduced by 73% with 10(-6) M ATRA and 3 x 10(-8) M LDL-ATRA. Furthermore, inhibition of invasion was correlated with a decrease in several factors: (1) secreted matrix metalloproteinase-9 and enzymes degrading type IV collagen and Matrigel films, and (2) tissue plasminogen activator. The results observed were found with a concentration of LDL-ATRA 30 times lower than that of ATRA. This could be due to the protective effect of LDL and to a better targeting of cancer cells through their LDL receptors. LDL-ATRA may therefore represent a new and potent inhibitor of invasion that could be developed for clinical trials.
 ...
PMID:Effects of all-trans-retinoic acid incorporated into low-density lipoprotein on invasive properties of multidrug-resistant MCF-7 spheroids. 1072 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>