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could be a beneficial therapy for the treatment of cancer. There are numerous approaches. One method may be the overexpression of SOCS pro teins to inhibit tumor growth by suppressing tumor promoting STATs. The second system is enhancing anti tumor immunity by silencing of SOCS in dendritic cells or CTLs. GSK J1 35 We showed that overexpression of SOCS1 can induce apoptosis of leukemic cells constitutively expressing activated JAK2. 16 Adenovirus mediated overexpression of SOCS1 can prevent HPV related cells transformation by inducing degra dation with the E7 oncoprotein. 9 SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and SOCS1 associates particularly with Cdh1, triggering its deg radation by the proteasome. 103 Enforced expression of SOCS1 leads to be resistant to transformation because of oncogenic induc tion.
104 SOCS3 overexpression also inhibits growth of non small lung cancer cells. 105 SOCS3 overexpression by adenoviral transfer enhanced the radio sensitivity of treated non small lung cancer cells. Infection of cells with oncolytic adenovirus CN305 SOCS3 and AdCN305 cell penetrating peptides SOCS3 resulted in dramatic cytotoxicity of liver tumor GSK J1 cells. Even so, no cyto toxic effect was observed in typical cells infected with these vectors. Infection of liver tumor cells with AdCN305 SOCS3 and AdCN305 cpp SOCS3 resulted in nearly complete inhibi tion of STAT3 phosphorylation and downregulation of cyclin D1 and Bcl xL. This study suggests that transfer of SOCS3 by an oncolytic adenovirus represents a potent method for cancer therapy.
106 SOCS3 overexpression suppressed growth of malig nant fibrous histiocytoma cell lines by inhibiting STAT3 and IL 6 production. Additionally, this study raised the possibility that small molecule inhibitors of JAK STAT could be therapeu tic for IL 6 producing tumors. 107 The tyrosine kinase inhibitor SKI II peptide, Tkip, was developed as a mimetic of SOCS RNA polymerase proteins and proficiently inhibits JAK2 mediated phosphorylation of STAT1: this peptide inhibited proliferation of prostate cancer cell lines, in which STAT3 is constitutively activated. 108 Upregulation of SOCS3 by some reagents may well also be SKI II therapeutic. Recently, platelet element 4 was found to induce SOCS3, thereby suppressing STAT3 activation, angio genesis, and growth and inducing apoptosis of myeloma cells.
109 Downregulation of SOCS gene GSK J1 expression by siRNA or by the expression of dominant damaging SOCS proteins to improve cytokine SKI II signaling could be beneficial for enhancing anti tumor immunity. The treatment of DCs with SOCS1 siRNA considerably enhanced the abil ity of DC based tumor vaccines to break self tolerance and to induce effective anti tumor immunity. 35,110,111 We have shown that adoptive transfer of SOCS1 deficient T cells strongly regressed transplanted tumor cells. All these studies are encouraging for the clinical application of novel therapeutic approaches to mimic or modulate expression and function of SOCS proteins. Concluding Remarks Over the past decade, following the discovery with the SOCS protein family members, we have extended our understanding with the structure and func tion of SOCS proteins.
Relating to cancer development, SOCS1 and SOCS3 are tightly linked to cancer cell proliferation, as well as cancer associated inflammation. In most circumstances, SOCS1 and SOCS3 silencing promoted carcinogenesis at different stages; therefore, overexpression of SOCS1 and SOCS3 or SOCS mimetics could be a therapuetic treatment. Even so, SOCS1 in DCs and most likely T cells GSK J1 suppresses anti tumor immunity; therefore, silencing SOCS1 in these cells could be therapeutic. Development of SOCS, based on structural analysis with the JAK/ SOCS complex, is very desirable. Vitamin A was recognized as an vital element in foods about a century ago and also a substantial body of information on the mechanisms that regulate its absorption and disposition in the body and on its biological functions has given that accumulated.
The vitamin plays important roles in embryonic development, vision, immune function, and tissue remodeling and metabolism. It really is generally believed that most of these functions are exerted not by the parental vitamin A molecule, SKI II retinol, but by active metabolites. Hence,11 cis retinal mediates phototransduction and is essential for vision, and all trans retinoic acid regulates gene transcription by activating the nuclear receptors retinoic acid receptors and peroxisome proliferator activated receptor B/. Other retinoids, most notably 9 cis retinoic acid, display transcriptional activities. Even so, when this isomer can efficiently activate the nuclear receptor retinoid X receptor, it has been difficult to establish whether it truly is in fact present in tissues that express RXR in vivo, aside from the pancreas. It therefore remains unclear whether 9 cis retinoic acid can be a physiologically meaningful RXR ligand. Vitamin A is obtained from the diet program either from animal sources, where it truly is present in the type of retinylesters, or from plants that contai