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首页> 外文期刊>Cytokine >TWEAK signals through JAK-STAT to induce tumor cell apoptosis
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TWEAK signals through JAK-STAT to induce tumor cell apoptosis

机译：TWEAK信号通过JAK-STAT诱导肿瘤细胞凋亡

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The TWEAK receptor Fn14 (TNFRSF12), a member of the TNF Receptor superfamily, can mediate many processes, including apoptosis. Fn14 agonists have therefore been the subject of interest as potential cancer therapeutics. In cell culture experiments, interferon gamma (IFNγ) is typically required for induction of apoptotic activity by either TWEAK or Fn14 agonistic antibodies in most cell lines. We have investigated the mechanism of IFNγ signaling and the role of JAK-STAT signaling in TWEAK/Fn14-mediated tumor cell killing. We found that IFNγ-mediated enhancement of tumor cell killing is JAK-STAT dependent, as JAK inhibitors block IFNγ-dependent TWEAK induced apoptosis. Exposure of tumor cells to IFNγ results in an increase in Fn14 expression on the cell surface, which may be a mechanism by which IFNγ induces sensitivity to TWEAK. In a reciprocal fashion, we observed that IFNγ receptor levels increase in response to TWEAK treatment in WiDr cells. Significantly, we found that TWEAK alone can induce STAT1 phosphorylation in WiDr tumor cells. Moreover, TWEAK induction of tumor cell apoptosis in WiDr cells in the absence of IFNγ is mediated by the JAK-STAT pathway. Correspondingly, we show that treatment of tumor bearing mice with mBIIB036, an Fn14 agonistic antibody, results in STAT1 phosphorylation in the tumors. Notably, the level of STAT1 phosphorylation appears to correlate with the degree of tumor growth inhibition by BIIB036 in vivo. Additionally, in WiDr cells, TWEAK induces a soluble factor, which we have identified as IFNβ, capable of independently inducing STAT1 phosphorylation when transferred to na?ve cells. Finally, either IFNα or IFNβ can partially substitute for IFNγ in sensitizing tumor cells to Fn14 agonists. In summary, we show that TWEAK/Fn14 can signal through the JAK-STAT pathway to induce IFNβ, and that the ability of TWEAK to induce tumor cell apoptosis is mediated by JAK-STAT signaling. We also demonstrate that IFNγ enhancement of TWEAK/FN14-mediated tumor cell death is JAK-dependent and may occur by IFNγ-dependent upregulation of Fn14 on tumor cells. These findings may have implications for the appropriately targeted clinical development of Fn14 agonists as anti-cancer therapy.
机译：TWEAK受体Fn14（TNFRSF12）是TNF受体超家族的成员，可以介导许多过程，包括凋亡。因此，Fn14激动剂已成为潜在的癌症治疗方法。在细胞培养实验中，大多数细胞系中TWEAK或Fn14激动性抗体诱导凋亡活性通常需要干扰素γ（IFNγ）。我们研究了IFNγ信号传导的机制以及JAK-STAT信号传导在TWEAK / Fn14介导的肿瘤细胞杀伤中的作用。我们发现IFNγ介导的肿瘤细胞杀伤增强作用是JAK-STAT依赖性的，因为JAK抑制剂可阻断IFNγ依赖性TWEAK诱导的细胞凋亡。肿瘤细胞暴露于IFNγ会导致细胞表面Fn14表达增加，这可能是IFNγ诱导对TWEAK敏感的机制。以对等的方式，我们观察到在WiDr细胞中响应TWEAK处理，IFNγ受体水平增加。重要的是，我们发现单独的TWEAK可以诱导WiDr肿瘤细胞中的STAT1磷酸化。此外，JAK-STAT途径介导在不存在IFNγ的情况下在WiDr细胞中TWEAK诱导肿瘤细胞凋亡。相应地，我们显示了用mBIIB036（一种Fn14激动性抗体）治疗荷瘤小鼠会导致STAT1磷酸化。值得注意的是，STAT1磷酸化的水平似乎与BIIB036在体内抑制肿瘤生长的程度有关。另外，在WiDr细胞中，TWEAK诱导了一种可溶性因子，我们已将其识别为IFNβ，当转移至幼稚细胞时能够独立诱导STAT1磷酸化。最后，在使肿瘤细胞对Fn14激动剂敏感的过程中，IFNα或IFNβ可以部分替代IFNγ。总而言之，我们表明TWEAK / Fn14可以通过JAK-STAT途径来诱导IFNβ，并且TWEAK诱导肿瘤细胞凋亡的能力是由JAK-STAT信号介导的。我们还证明，TWEAK / FN14介导的肿瘤细胞死亡的IFNγ增强是JAK依赖性的，可能通过Fn14对肿瘤细胞的IFNγ依赖性上调而发生。这些发现可能对Fn14激动剂作为抗癌疗法的适当靶向临床开发有影响。

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