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1 Internal Medicine, The Ohio State University, Columbus, Ohio, United States
2 Physiology, The Ohio State University, Columbus, Ohio, United States; Internal Medicine, The Ohio State University, Columbus, Ohio, United States
3 Columbus , Ohio, United States; Internal Medicine, The Ohio State University, Columbus, Ohio, United States
4 Columbus, Ohio, United States; Internal Medicine, The Ohio State University, Columbus, Ohio, United States
* To whom correspondence should be addressed. E-mail: govindasamy.Ilangovan{at}osumc.edu.
Doxorubicin (DOX) and its derivatives are used as chemotherapeutic drugs to treat cancer patients. However, prolonged use of these drugs has been found to cause dilative cardiomyopathy and congestive heart failure due to the production of DOX-mediated reactive oxygen species (ROS). Thus, various preventive modalities have been developed to avoid this untoward side effect. In this paper, using cardiac cells, we report that the DOX- mediated oxidant-induced toxicity could be minimized by hyperthermia-induced small heat shock protein Hsp27; that is, this protein acts as an endogenous antioxidant against DOX-derived oxidants such as H2O2. Heat shock-induced Hsp27 was found to act as an anti-apoptotic protein (reducing ROS and Bax/Bcl2 ratio) against the DOX, and its phosphorylated isoforms were found to stabilize the F-actin remodeling in DOX treated cardiac cells and hence attenuating the toxicity. Further, protein kinase assays and proteomic analyses suggested that higher expression of Hsp27 and its phosphorylation are responsible for the observed protection in the heat-shocked cells. 2D gel electrophoresis showed 6 isoforms (non-phosphorylated and phosphorylated) of Hsp27. MALDI-TOF analyses showed two isoforms of Hsp27 (
and 
) are phosphorylated by various protein kinases. The S-15 and S-85 phosphorylation of Hsp27 by MAPKAP-2 was found to be the key mechanism in reducing apoptosis and facilitating F-actin remodeling. In conclusion, the present study illustrates that hyperthermia offers protection from DOX-induced cell death through induction and phosphorylation of Hsp27, and its anti-apoptotic and actin remodeling activities.
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