The heat shock protein 90 inhibitor 17-AAG suppresses growth and induces apoptosis in human cholangiocarcinoma cells
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SHORT COMMUNICATION
The heat shock protein 90 inhibitor 17-AAG suppresses growth and induces apoptosis in human cholangiocarcinoma cells Jianjun Zhang • Zhichao Zheng • Yan Zhao Tao Zhang • Xiaohu Gu • Wei Yang
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Received: 2 June 2012 / Accepted: 18 August 2012 / Published online: 7 September 2012 Ó Springer-Verlag 2012
Abstract The aim of this study was to investigate the effects of 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a heat shock protein 90 (HSP90) inhibitor, on the proliferation, cell cycle, and apoptosis of human cholangiocarcinoma (CCA) cells. Cell proliferation and cell cycle distribution were measured by the MTT assay and flow cytometry analysis, respectively. Induction of apoptosis was determined by flow cytometry and Hoechst staining. The expressions of cleaved poly ADP-ribose polymerase (PARP), Bcl-2, Survivin, and Cyclin B1 were detected by Western blot analysis. The activity of caspase3 was also examined. We found that 17-AAG inhibited cell growth and induced G2/M cell cycle arrest and apoptosis in CCA cells together with the down-regulation of Bcl-2, Survivin and Cyclin B1, and the up-regulation of cleaved PARP. Moreover, increased caspase-3 activity was also observed in CCA cells treated with 17-AAG. In conclusion, our data suggest that the inhibition of HSP90 function by 17-AAG may provide a promising therapeutic strategy for the treatment of human CCA. Keywords HSP90 17-AAG Cell cycle arrest Apoptosis Cholangiocarcinoma
J. Zhang (&) Z. Zheng Y. Zhao T. Zhang X. Gu W. Yang The Third Department of Surgery, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang 110042, Liaoning, People’s Republic of China e-mail: [email protected]
Introduction Cholangiocarcinoma (CCA) is a rare but devastating malignancy arising from the epithelial cells of the bile tracts [1]. The incidence of CCA is increasing worldwide and the highest rates occur in China, northeast of Thailand, and other parts of Southeast Asia [2]. Although it has been related to predisposing genetic and environmental triggers, the etiology of CCA is still largely unknown. Because CCA is notoriously difficult to diagnose, it is generally associated with a high mortality and poor prognosis [3]. Nowadays, complete surgical resection remains the only therapeutic option with a chance of cure. However, the 5-year survival rate of patients underwent surgical resection has been reported as low as 11 % [4]. Lack of effective adjuvant therapy is one of the biggest challenges for the treatment of CCA [5]. Heat shock protein 90 (HSP90) is a ubiquitous molecular chaperone that participates in the folding, assembly, activation, maturation, and stabilization of many other proteins, referred to as ‘‘clients’’ [6, 7]. These client proteins include kinases, transcription factors, signaling molecules, and many other proteins involved in a wide variety of biological processes [8, 9]. HSP90 is engaged in the regulation of the conformation, stability, function of some key oncogenic client proteins, thereby indirectly mai
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