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首页> 外文期刊>Journal of Cellular Physiology >Exposure of normal human melanocytes to a tumor promoting phorbol ester reverses growth suppression by transforming growth factor beta.
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Exposure of normal human melanocytes to a tumor promoting phorbol ester reverses growth suppression by transforming growth factor beta.

机译：正常人体黑色素细胞肿瘤的风险促进佛波醇酯反转增长通过转化生长因子β抑制。

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Transforming growth factor-beta (TGF-beta), a potent inhibitor of normal melanocyte growth, does not significantly suppress growth of melanoma cells. The mechanism of melanocyte desensitization to TGF-beta in the transformation process remains largerly unknown. We investigated whether the tumor promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) may induce melanocyte resistance to TGF-beta. Cell proliferation and DNA synthesis of normal human melanocytes were strongly inhibited by TGF-beta, whereas in the presence of TPA remained largerly unaffected. The inactive phorbol ester 4alpha-phorbol 12,13 didecanoate did not modify the TGF-beta antiproliferative effect, whereas the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol counteracted TGF-beta effects. Protein kinase C (PKC) is the major cellular receptor of tumor promoting phorbol esters. PKC-alpha expression and phosphorylation were almost completely downregulated under combined treatment with TGF-beta + TPA at 24 and 72 h, as shownby immunoblots. Confocal microscopy demonstrated that TGF-beta-induced nuclear accumulation of PKC-alpha was abolished in the presence of TPA at the same time points. The selective PKC inhibitor Ro-31-8220 weakened the TGF-beta antiproliferative effect. Smads are central mediators for TGF-beta signal transduction. Smad-dependent transcriptional activity was suppressed in TGF-beta-treated melanocytes in the presence of TPA, as well as in ALK5 (constitutively active type I TGF-beta receptor)- or Smad3 + Smad4-transfected melanocytes in the presence of Ro-31-8220. In addition, an antisense oligodeoxynucleotide against PKC-alpha abolished TGF-beta-driven Smad-mediated transcription. These findings show that tumor promoting phorbol esters induce melanocyte resistance to TGF-beta, associated with downregulation of PKC-alpha and suppression of Smad-dependent transcription. This may represent an important mechanism for expansion of melanocytes exposed to PKC-targeting tumor promoters.
机译：转化生长因子(及)正常黑素细胞增长的有效抑制剂,不显著抑制增长的黑色素瘤细胞。脱敏的鉴定及转换过程仍可大幅度未知。肿瘤是否促进佛波醇酯12-O-tetradecanoylphorbol-13-acetate (TPA)及诱导黑素细胞抵抗。核扩散和正常人类的DNA合成黑色素细胞被鉴定及强烈抑制,而在TPA仍可大幅度的存在不受影响。4 alpha-phorbol 12、13 didecanoate没有修改鉴定及抗增殖效果,而甘油二酯的模拟1-oleoyl-2-acetyl-sn-glycerol中和及影响。促进肿瘤的主要细胞受体佛波醇酯。磷酸化几乎完全表达下调下综合治疗及在24和72 h + TPA, shownby免疫印迹。TGF-beta-induced核的积累PKC-alpha TPA的存在被废除同样的时间点。ro - 31 - 8220削弱了鉴定及抗增殖效果。介质及信号转导。Smad-dependent转录活动在TGF-beta-treated抑制黑色素细胞在ALK5 TPA的存在,以及(持续活跃的I型及受体)或Smad3 + Smad4-transfected黑色素细胞ro - 31 - 8220。对PKC-alpha oligodeoxynucleotide废除TGF-beta-driven Smad-mediated转录。这些发现表明肿瘤促进佛波醇酯诱导黑素细胞及阻力,PKC-alpha和差别与对这些Smad-dependent转录抑制。可能代表一个重要的机制黑色素细胞暴露于PKC-targeting的扩张肿瘤促进剂。

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