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Celecoxib-mediated activation of endoplasmic reticulum stress induces de novo ceramide biosynthesis and apoptosis in hepatoma HepG2 cells
Hyo Jin Maeng1, Jae-Hwi Song1, Goon-Tae Kim1, Yoo-Jeong Song1, Kangpa Lee2, Jae-Young Kim1, Tae-Sik Park1,*
1Department of Life Science, Gachon University,
2Department of Physiology, Konkuk University
Ceramides are the major sphingolipid metabolites involved in cell survival and apoptosis. When HepG2 hepatoma cells were treated with celecoxib, the expression of the genes in de novo sphingolipid biosynthesis and sphingomyelinase pathway was upregulated and cellular ceramide was elevated. In addition, celecoxib induced endoplasmic reticulum (ER) stress in a time-dependent manner. SPTLC2, a subunit of serine palmitoyltransferase, was overexpressed by adenovirus. Adenoviral overexression of SPTLC2 (AdSPTLC2) decreased cell viability of HEK293 and HepG2 cells. In addition, AdSPTLC2 induced apoptosis via the caspase-dependent apoptotic pathway and elevated cellular ceramide, sphingoid bases, and dihydroceramide. However, overexpression of SPTLC2 did not induce ER stress. Collectively, celecoxib activates de novo sphingolipid biosynthesis and the combined effects of elevated ceramide and transcriptional activation of ER stress induce apoptosis. However, activation of de novo sphingolipid biosynthesis does not activate ER stress in hepatoma cells and is distinct from the celecoxib-mediated activation of ER stress.
Abstract, Accepted Manuscript(in press) [Submitted on November 30, 2016, Accepted on February 6, 2017]
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