TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade
| Autor: | Hye Jin Choi, Soo Jin Choi, Dongxu Kang, Geun-Hyeok Oh, Zhezhu Han, Suwan Ko, Suyeon Je, Jihyun Lee, Jae J. Song, Yeonsoo Joo |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death MAP Kinase Kinase 4 p38 mitogen-activated protein kinases Clinical Biochemistry Down-Regulation lcsh:Medicine MAP Kinase Kinase Kinase 5 Biochemistry p38 Mitogen-Activated Protein Kinases Article lcsh:Biochemistry 03 medical and health sciences Downregulation and upregulation Transforming Growth Factor beta Neoplasms Humans ASK1 lcsh:QD415-436 Phosphorylation RNA Small Interfering Molecular Biology Protein kinase B Cell Death Chemistry lcsh:R Intracellular Signaling Peptides and Proteins Membrane Proteins Endoplasmic Reticulum Stress Cell biology Oncogene Protein v-akt 030104 developmental biology A549 Cells NADPH Oxidase 4 Cancer cell Unfolded protein response Molecular Medicine Signal transduction Reactive Oxygen Species Signal Transduction |
| Zdroj: | Experimental and Molecular Medicine, Vol 50, Iss 12, Pp 1-19 (2018) Experimental & Molecular Medicine |
| ISSN: | 2092-6413 1226-3613 |
| Popis: | 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. Cancer: Tipping the signaling balance Reducing the levels of the multifunctional protein transforming growth factor (TGF)-β in cancer cells prevents tumor growth in mice. Previous studies have shown that high levels of TGF-β in cancerous tissue are associated with accelerated disease progression. Hye Jin Choi and Jae J Song at Yonsei University in Seoul, South Korea, and colleagues infected cancer cells with genetically modified viruses that reduced the expression of the gene encoding TGF-β. The resulting decrease in TGF-β protein led to cell death by stimulating the production of reactive oxygen species and signaling through the apoptosis signal-regulating kinase 1 (ASK1) pathway. When tumor-bearing mice were infected with these modified viruses, their overall survival was improved. Further understanding the mechanisms through which TGF-β regulates cancer cell survival will contribute to the development of new approaches in cancer treatment. |
| Databáze: | OpenAIRE |
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