BMB Reports 2017; 50(3): 150-155  
Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways
Hye Jung Ihn1, Ju Ang Kim1, Yong Chul Bae2, Hong-In Shin1, Moon-Chang Baek3,* & Eui Kyun Park1,*
Departments of 1Oral Pathology and Regenerative Medicine, 2Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 41940, 3Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, Daegu 41944, Korea
Correspondence to: Moon-Chang Baek, Tel: +82-53-420-4948; Fax: +82-53-420-4944; E-mail: mcbaek@knu.ac.kr, Eui Kyun Park, Tel: +82-53-420-4995; Fax: +82-53-428-4995; E-mail: epark@knu.ac.kr
Received: December 21, 2016; Published online: March 31, 2017.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

Abstract
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 overexpression 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.
Keywords: Afatinib, Bone resorption, Differentiation, Osteoclast, RANK signaling


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