TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade
TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade
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DOI：
10.1038/s12276-018-0189-8
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发表时间：
2018-12-06
影响因子：
12.8
通讯作者：
Song, Jae J.
中科院分区：
文献类型：
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作者：
Han, Zhezhu;Kang, Dongxu;Song, Jae J.
转化生长因子（TGF）-β信号越来越被认为是癌症的关键驱动因素。在进行性癌症组织中，TGF-β促进肿瘤形成，其表达增加通常与癌症恶性程度相关。在这项研究中，我们利用腺病毒表达针对TGF-β 1和TGF-β 2的短发夹RNA来研究TGF-β下调在癌细胞死亡中的作用。我们发现TGF-β的下调增加了几种SAPKs的磷酸化，如p38和JNK。此外，活性氧（ROS）的产生也增加了TGF-β下调，这触发Akt失活和NOX 4增加衍生的ROS在癌细胞类型特异性的方式。我们还揭示了与SAPKs相关的TGF-β下调反应中大量基因波动的可能性。Trx和GSTM 1（编码与ASK 1结合的抑制性蛋白）的表达水平降低，可能是Smad复合物蛋白改变易位的结果，而不是ROS产生。相反，ROS和ROS介导的ER应激都是ASK 1和Trx或GSTM 1之间相互作用减少的原因。通过这些途径，ASK 1被激活并通过p38/JNK激活和（或）诱导ER应激诱导细胞毒性肿瘤细胞死亡。
Transforming growth factor (TGF)-beta signaling is increasingly recognized as a key driver in cancer. In progressive cancer tissues, TGF-beta promotes tumor formation, and its increased expression often correlates with cancer malignancy. In this study, we utilized adenoviruses expressing short hairpin RNAs against TGF-beta 1 and TGF-beta 2 to investigate the role of TGF-beta downregulation in cancer cell death. We found that the downregulation of TGF-beta increased the phosphorylation of several SAPKs, such as p38 and JNK. Moreover, reactive oxygen species (ROS) production was also increased by TGF-beta downregulation, which triggered Akt inactivation and NOX4 increase-derived ROS in a cancer cell-type-specific manner. We also revealed the possibility of substantial gene fluctuation in response to TGF-beta downregulation related to SAPKs. The expression levels of Trx and GSTM1, which encode inhibitory proteins that bind to ASK1, were reduced, likely a result of the altered translocation of Smad complex proteins rather than from ROS production. Instead, both ROS and ROS-mediated ER stress were responsible for the decrease in interactions between ASK1 and Trx or GSTM1. Through these pathways, ASK1 was activated and induced cytotoxic tumor cell death via p38/JNK activation and (or) induction of ER stress.