Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteins belonging to the suppressors of cytokine signaling (SOCS) family have been shown to regulate cytokine signal transduction in various cell types but their role in modulating the response of immune cells to IFN-alpha has not been fully explored. We hypothesized that SOCS proteins would inhibit the antitumor activity of IFN-alpha-stimulated immune cells. Transcripts for SOCS1, SOCS2, SOCS3, and cytokine-inducible Src homology 2-containing protein were identified in total human PBMC (PBMCs, NK cells, and T cells) within 1-2 h of stimulation with IFN-alpha (10(3)-10(5) U/ml). Immunoblot analysis confirmed the expression of these factors at the protein level. Transcripts for SOCS proteins were rapidly but variably induced in PBMCs from patients with metastatic melanoma following the i.v. administration of IFN-alpha-2b (20 million units/m(2)). Overexpression of SOCS1 and SOCS3, but not SOCS2, in the Jurkat T cell line inhibited IFN-alpha-induced phosphorylated STAT1 and the transcription of IFN-stimulated genes. Conversely, small inhibitory RNA-mediated down-regulation of SOCS1 and SOCS3 in Jurkat cells and normal T cells enhanced the transcriptional response to IFN-alpha. Loss of SOCS1 or SOCS3 in murine immune effectors was associated with enhanced IFN-induced phosphorylated STAT1, transcription of IFN-stimulated genes, and antitumor activity. Of note, IFN-alpha treatment eliminated melanoma tumors in 70% of SOCS1-deficient mice, whereas IFN-treated SOCS-competent mice all died. The antitumor effects of IFN-alpha in tumor-bearing SOCS1-deficient mice were markedly inhibited following depletion of CD8(+) T cells. These results indicate that the antitumor response of immune effector cells to exogenous IFN-alpha is regulated by SOCS proteins.
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PMID:IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. 1740 64

Malignant melanoma arises through a series of genetic and epigenetic events. A more profound understanding of the biology of metastatic melanoma should greatly aid in the development of new and effective treatments. Currently, avenues being pursued to improve treatment of metastatic melanoma include dendritic cell vaccines and other vaccination strategies, tyrosine kinase inhibitors, adoptive transfer of ex vivo stimulated T cells, and, as reviewed here, epigenetic approaches. The "methylator phenotype", with inactivation by promoter hypermethylation of numerous genes in malignant melanoma cell lines and primary tumors (p16, PTEN, RASSF1, estrogen receptor, retinoic acid receptor beta, SOCS1 and -2, MGMT etc.) offers a strong rationale for treatment approaches based on the use of DNA demethylating agents. The clinical literature on treatment of metastasized malignant melanoma with either 5-azacytidine or 5-aza-2'-deoxycytidine (decitabine) is reviewed. Future trials in malignant melanoma with these compounds might profit from prolonged low-dose exposure, since they unfold their full effects not immediately but with a certain delay, which may be associated with their DNA demethylating activity. Combinations of DNA demethylation agents with either histone deacetylase inhibitors, interleukin-2, chemotherapy or tamoxifen have been embarked on both in in vitro models of melanoma and recent clinical trials. The in vitro synergism between inhibitors of DNA methylation and histone deacetylation strongly invites a systematic study of combinations of both groups of agents. Up-regulation of cancer testis antigens by epigenetic therapy in melanoma also offers a very strong rationale to place these drugs and schedules within a larger treatment concept of immunotherapy which may include also T cell activation e.g. by interleukin-2, and vaccination strategies. In conclusion, the epigenome of malignant melanoma, with a well-established in vitro reversal potential, holds promise as a novel molecular target.
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PMID:Epigenetic lesions in malignant melanoma. 1828 47