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Heat Shock Protein 27 Protects L929 Cells from Cisplatin-Induced Apoptosis by Enhancing Akt Activation and Abating Suppression of Thioredoxin Reductase Activity

Authors' Affiliations: ¹ Institute of Biophysics, Chinese Academy of Science, Graduate School of the Chinese Academy of Sciences, Beijing, P.R. China and ² Division of Nitric Oxide and Inflammatory Medicine, E-Institutes of Shanghai Universities (Shanghai University of Traditional Chinese Medicine), Shanghai, P.R. China

Requests for reprints: Xun Shen, Institute of Biophysics, Chinese Academy of Sciences, 15# Datun Road, Chaoyang District, Beijing 100101, P.R. China. Phone: 86-10-6488-8574; Fax: 86-10-6487-1293; E-mail: shenxun{at}sun5.ibp.ac.cn.

Purpose: Heat shock protein 27 (Hsp27) is up-regulated in multiple malignancies and implicated in cisplatin resistance. It is attempted to know how Hsp27 endues cell with cisplatin resistance by interfering with upstream of both apoptosis signal–regulating kinase 1 (ASK1)/p38 mitogen-activated protein kinase–activated apoptotic signaling and serine/threonine kinase Akt-dependent survival signaling.

Experimental Design: The mouse L929 cells stably transfected with human Hsp27 or its dominant-negative mutant and the human cervical cancer HeLa cells transfected with Hsp27 siRNA were used. The cisplatin-induced apoptosis and activation of ASK1, p38, and Akt were compared in control cells, cells overexpressing Hsp27, and cells with their endogenous Hsp27 knocked down.

Results: Hsp27 effectively protected the cells from cisplatin-induced DNA fragmentation. The p38 inhibitors obviously decreased whereas Akt inhibitors markedly increased the apoptotic fraction in cisplatin-treated cells. Overexpression of Hsp27 doubly enhanced the drug-induced Akt activation while substantially depressing the drug-induced activation of ASK1 and p38. Knockdown of the endogenous Hsp27 in HeLa cells resulted in the effects opposite to that observed in the Hsp27-overexpressing cells. Enhancement of Akt activation is associated with complex formation between Akt and Hsp27, whereas depression of ASK1/p38 activation is attributed to a reversion of the drug-induced inhibition of thioredoxin reductase activity and subsequent oxidation of thioredoxin.

Conclusions: Hsp27 endues cells with cisplatin resistance via depression of the drug-induced ASK1/p38 activation and enhancement of the drug-induced Akt activation. This study revealed the intervention of Hsp27 in upstream of both ASK1/p38 apoptotic signaling and phosphatidylinositol 3-kinase/Akt survival signaling. Therefore, the inhibition of Hsp27 may be a novel strategy of cancer chemotherapy.

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