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首页> 外文期刊>European cytokine network >Activation of two distinct anti-proliferative pathways, apoptosis and p38 MAP kinase-dependent cell cycle arrest, by tumor necrosis factor in human melanoma cell line A375.
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Activation of two distinct anti-proliferative pathways, apoptosis and p38 MAP kinase-dependent cell cycle arrest, by tumor necrosis factor in human melanoma cell line A375.

机译：人类黑素瘤细胞系A375中的肿瘤坏死因子激活了两个不同的抗增殖途径，即凋亡和p38 MAP激酶依赖性细胞周期阻滞。

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The proliferation of human melanoma cell line A375-6 cells is inhibited by several cytokines, including interleukin-1 (IL-1). A375-R8 cells, a subclone of A375-6, are resistant to IL-1-induced growth inhibition. The proliferation of both cell lines is inhibitable by tumor necrosis factor (TNF). In this study, we characterized the mechanisms of TNF-induced growth inhibition. TNF-induced growth inhibition in both cell lines was partially suppressed by a selective p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), whereas a combination of SB203580 and Z-VAD-fmk, an inhibitor for a wide range of caspases, completely blocked TNF-induced growth inhibition, indicating that TNF-induced growth inhibition is mediated by both p38 MAPK and caspases. However, Z-VAD-fmk alone suppressed TNF-induced growth inhibition in A375-R8, but not A375-6, cells, suggesting that there may exist a TNF-induced anti-apoptotic mechanism in A375-6 cells which is lost or mutated in A375-R8 cells. Evidence in support of this notion includes (1) TNF-induced apoptosis only in A375-R8, but not A375-6 cells; (2) cycloheximide enabled TNF to induce apoptosis even in A375-6 cells; and (3) somatic hybrid cells between A375-6 and A375-R8 cells are resistant to TNF-induced apoptosis. Since TNF-induced NF-kappa B activation, cell cycle arrest, RB dephosphorylation, and E2F downregulation are indistinguishable in both cell lines, none of these factors is likely to be involved in the TNF-induced anti-apoptotic mechanism in A375-6 cells. Our results indicate that TNF activates two distinct anti-proliferative pathways including p38 MAPK-dependent cell cycle arrest and caspase-mediated apoptosis, as well as an anti-apoptotic mechanism in melanoma cells.
机译：人黑素瘤细胞系A375-6细胞的增殖受到几种细胞因子（包括白介素1（IL-1））的抑制。 A375-R8细胞是A375-6的亚克隆，对IL-1诱导的生长抑制具有抗性。肿瘤坏死因子（TNF）可抑制两种细胞系的增殖。在这项研究中，我们表征了TNF诱导的生长抑制的机制。选择性p38丝裂原活化蛋白激酶（MAPK）抑制剂（SB203580）可以部分抑制TNF诱导的两种细胞系的生长抑制，而SB203580和Z-VAD-fmk（多种胱天蛋白酶）抑制剂的组合，完全阻断了TNF诱导的生长抑制，表明TNF诱导的生长抑制是由p38 MAPK和胱天蛋白酶介导的。但是，单独的Z-VAD-fmk抑制了TNF诱导的A375-R8细胞的生长抑制，而没有抑制A375-6的细胞生长，这提示TNF诱导的A375-6细胞中可能存在丢失或突变的抗凋亡机制。在A375-R8细胞中支持该观点的证据包括：（1）TNF诱导的仅在A375-R8细胞中诱导的凋亡，而在A375-6细胞中不诱导; （2）环己酰亚胺使TNF即使在A375-6细胞中也能诱导凋亡。 （3）A375-6和A375-R8细胞之间的体细胞杂交细胞对TNF诱导的凋亡具有抗性。由于在两种细胞系中都无法区分TNF诱导的NF-κB活化，细胞周期停滞，RB脱磷酸化和E2F下调，因此这些因素均可能与A375-6细胞的TNF诱导的抗凋亡机制无关。 。我们的结果表明，TNF激活两个不同的抗增殖途径，包括p38 MAPK依赖性细胞周期阻滞和caspase介导的细胞凋亡，以及黑色素瘤细胞的抗凋亡机制。

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