Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 112, Issue 2, Pages 453-462Publisher
WILEY
DOI: 10.1002/jcb.22927
Keywords
CHONDROSARCOMA; MITOCHONDRIA; ROS; ER; GRP78
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Funding
- National Science Council of Taiwan [NSC99-2320-B-039-003-MY3]
- China Medical University [CMU99-NSC-05]
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Chondrosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. The aim of this study was to elucidate the mechanism of the novel Combretastatin A-4 derivative, 2-(furanyl)-5-(pyrrolidinyl)-1-(3,4,5-trimethoxybenzyl)benzoimidazole (FPTB)-induced human chondrosarcoma cells apoptosis. FPTB induced cell apoptosis in human chondrosarcoma cell line but not primary chondrocytes. FPTB induced up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bel-XL and dysfunction of mitochondria in chondrosarcoma. FPTB also triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels. We found that FPTB increased glucose-regulated proteins (GRP)78 but not GRP94 expression. In addition, treatment of cells with FPTB induced calpain expression and activity. Transfection of cells with GRP78 or calpain siRNA reduced FPTB-mediated cell apoptosis. Therefore, FPTB-induced apoptosis in chondrosarcoma cells through the mitochondria dysfunction and involves caspase-9 and caspase-3-mediated mechanism. FPTB also induced cell death mediated by increasing ER stress, GPR78 activation, and Ca2+ release, which subsequently triggers calpain, caspase-12 and caspase-3 activity, resulting in apoptosis. J. Cell. Biochem. 112: 453-462, 2011. (C) 2010 Wiley-Liss, Inc.
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