Mitigated NSAID-induced apoptotic and autophagic cell death with Smad7 overexpression
- Authors
- Lee, Ho-Jae; Park, Jong Min; Hahm, Ki Baik
- Issue Date
- Jan-2017
- Publisher
- JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION
- Keywords
- NSAID; gastrointestinal damages; Smad7; apoptosis; autophagy
- Citation
- JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION, v.60, no.1, pp.55 - 62
- Journal Title
- JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION
- Volume
- 60
- Number
- 1
- Start Page
- 55
- End Page
- 62
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/6541
- DOI
- 10.3164/jcbn.16-69
- ISSN
- 0912-0009
- Abstract
- Non-steroidal anti-inflammatory drugs damaged gastrointestinal mucosa in cyclooxygenase-dependent and-independent pathway, among which apopototic or autophagic cell death in gastrointestinal cells might be one of key cytotoxic mechanisms responsible for NSAID-induced damages. Therefore, alleviating this cell death after NSAIDs can be a rescuing strategy. In this study, we explored the role of Smad7 on NSAID-induced cytotoxicity in gastric epithelial cells. Using RGM1 cells, we have compared biological changes between mock-transfected and Smad7-overexpressed cells. As results, significantly decreased cytotoxicity accompanied with decreased levels of cleaved caspase-3 and poly (ADP-ribose) polymerase, Bax, and autophagic vesicles concurrent with decreased expressions of autophagy protein 5 and microtubule-associated protein light chain 3B-II were noted in Smad7overexpressed cells with indomethacin administration compared to mock-transfected cells. Contrast to mitigated apoptotic execution, anti-apoptotic Bcl-2 and Beclin-1 were significantly increased in Smad7-overexpressed cells compared to mock-transfected cells. Smad7 siRNA significantly reversed these protective actions of Smad7 against indomethacin, in which p38 mitogen-activated protein kinase was significantly intervened. Furthermore, indomethacin-induced Smad7 degradation through ubiquitinproteasome pathway was relevant to increased cytotoxicity, while chloroquine as autophagy inhibitor significantly attenuated indomethacin-induced cytotoxicity through Smad7 preservation via repressed ubiquitination. Conclusively, either genetic over expression or pharmacological induction of Smad7 significantly attenuated indomethacin-induced gastric cell damages.
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