Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
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TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade

  • Han, Zhezhu (Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Kang, Dongxu (Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Joo, Yeonsoo (Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Lee, Jihyun (Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Oh, Geun-Hyeok (Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Choi, Soojin (Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Ko, Suwan (Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Je, Suyeon (Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Choi, Hye Jin (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Song, Jae J. (Institute for Cancer Research, Yonsei University College of Medicine)
  • Received : 2018.01.07
  • Accepted : 2018.09.11
  • Published : 2018.12.30
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Abstract

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.

Keywords

Acknowledgement

Supported by : Korea Drug Development Fund, National Research Foundation of Korea (NRF)

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