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KMID : 0620920180500120162
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Experimental & Molecular Medicine
2018 Volume.50 No. 12 p.162 ~ p.162
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TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade
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Han Zhezhu
Kang Dongxu
Joo Yeon-Soo
Lee Ji-Hyun
Oh Geun-Hyeok
Choi Soo-Jin
Ko Su-Wan
Je Su-Yeon
Choi Hye-Jin
Song Jae-J.
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Abstract
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Transforming growth factor (TGF)-β signaling is increasingly recognized as a key driver in cancer. In progressive cancer tissues, TGF-β promotes tumor formation, and its increased expression often correlates with cancer malignancy. In this study, we utilized adenoviruses expressing short hairpin RNAs against TGF-β1 and TGF-β2 to investigate the role of TGF-β downregulation in cancer cell death. We found that the downregulation of TGF-β increased the phosphorylation of several SAPKs, such as p38 and JNK. Moreover, reactive oxygen species (ROS) production was also increased by TGF-β 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-β 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.
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KEYWORD
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Medical research, Oncogenes
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