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Detection of Necroptosis in Ligand-Mediated and Hypoxia-Induced Injury of Hepatocytes Using a Novel Optic Probe-Detecting Receptor-Interacting Protein (RIP)1/RIP3 Binding
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| Title: | Detection of Necroptosis in Ligand-Mediated and Hypoxia-Induced Injury of Hepatocytes Using a Novel Optic Probe-Detecting Receptor-Interacting Protein (RIP)1/RIP3 Binding |
| Authors: | Haga, Sanae Browse this author →KAKEN DB | | Kanno, Akira Browse this author | | Ozawa, Takeaki Browse this author | | Morita, Naoki Browse this author | | Asano, Mami Browse this author | | Ozaki, Michitaka Browse this author →KAKEN DB |
| Keywords: | Regulated cell death | | Necroptosis | | Reactive oxygen species (ROS) | | Fas ligand | | Hypoxia/reoxygenation |
| Issue Date: | 10-Apr-2018 |
| Publisher: | Cognizant Communication Corporation |
| Journal Title: | Oncology research |
| Volume: | 26 |
| Issue: | 3 |
| Start Page: | 503 |
| End Page: | 513 |
| Publisher DOI: | 10.3727/096504017X15005102445191 |
| PMID: | 28770700 |
| Abstract: | Liver injury is often observed in various pathological conditions including posthepatectomy state and cancer chemotherapy. It occurs mainly as a consequence of the combined necrotic and apoptotic types of cell death. In order to study liver/hepatocyte injury by the necrotic type of cell death, we studied signal-regulated necrosis (necroptosis) by developing a new optic probe for detecting receptor-interacting protein kinase 1(RIP)/RIP3 binding, an essential process for necroptosis induction. In the mouse hepatocyte cell line, TIB-73 cells, TNF-alpha/cycloheximide (T/C) induced RIP1/3 binding only when caspase activity was suppressed by the caspase-specific inhibitor z-VAD-fmk (zVAD). T/C/zVAD-induced RIP1/3 binding was inhibited by necrostatin-1 (Nec-1), an allosteric inhibitor of RIP1. The reduced cell survival by T/C/zVAD was improved by Nec-1. These facts indicate that T/C induces necroptosis of hepatocytes when the apoptotic pathway is inhibited/unavailable. FasL also induced cell death, which was only partially inhibited by zVAD, indicating the possible involvement of necroptosis rather than apoptosis. FasL activated caspase 3 and, similarly, induced RIP1/3 binding when the caspases were inactivated. Interestingly. FasL-induced RIP1/3 binding was significantly suppressed by the antioxidants Trolox and N-acetyl cysteine (NAC), suggesting the involvement of reactive oxygen species (ROS) in FasL-induced necroptotic cellular processes. H2O2 . by itself. induced RIP1/3 binding that was suppressed by Nec-1. but not by zVAD. Hypoxia induced RIP1/3 binding after reoxygenation, which was suppressed by Nec-1 or by the antioxidants. Cell death induced by hypoxia/ reoxygenation (H/R) was also improved by Nec-1. Similar to H2O2 , H/R did not require caspase inhibition for RIP1/3 binding, suggesting the involvement of a caspase-independent mechanism for non-ligand-induced and/or redox-mediated necroptosis. These data indicate that ROS can induce necroptosis and mediate the FasL- and hypoxia-induced necroptosis via a molecular mechanism that differs from a conventional caspase-dependent pathway. In conclusion. necroptosis is potentially involved in liver/hepatocyte injury induced by oxidative stress and FasL in the absence of apoptosis. |
| Rights: | http://creativecommons.org/licenses/by-nc/3.0/ |
| Type: | article |
| URI: | http://hdl.handle.net/2115/70691 |
| Appears in Collections: | 保健科学院・保健科学研究院 (Graduate School of Health Sciences / Faculty of Health Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 尾崎 倫孝
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