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Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

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Abstract

Cisplatin is a highly successful and widely used chemotherapy for the treatment of various solid malignancies in both adult and pediatric patients. Side effects of cisplatin treatment include nephrotoxicity and ototoxicity. Cisplatin ototoxicity results from damage to and death of cells in the inner ear, including sensory hair cells. We showed previously that heat shock inhibits cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. Since heat shock protein 70 (HSP70) is the most upregulated HSP in response to heat shock, we investigated the role of HSP70 as a potential protectant against cisplatin-induced hair cell death. Our data using utricles from HSP70 −/− mice indicate that HSP70 is necessary for the protective effect of heat shock against cisplatin-induced hair cell death. In addition, constitutive expression of inducible HSP70 offered modest protection against cisplatin-induced hair cell death. We also examined a second heat-inducible protein, heme oxygenase-1 (HO-1, also called HSP32). HO-1 is an enzyme responsible for the catabolism of free heme. We previously showed that induction of HO-1 using cobalt protoporphyrin IX (CoPPIX) inhibits aminoglycoside-induced hair cell death. Here, we show that HO-1 also offers significant protection against cisplatin-induced hair cell death. HO-1 induction occurred primarily in resident macrophages, with no detectable expression in hair cells or supporting cells. Depletion of macrophages from utricles abolished the protective effect of HO-1 induction. Together, our data indicate that HSP induction protects against cisplatin-induced hair cell death, and they suggest that resident macrophages mediate the protective effect of HO-1 induction.

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Acknowledgments

Our thanks to Dr. Mark Warchol for many helpful conversations, for participation in pilot studies using CX3CR1GFP/+ utricles and for guidance regarding the liposomal clodronate for these studies.

Thanks to Lindsey May for help with qRT-PCR experiments. Thanks to Dr. Suhua Sha for graciously sharing her lab space during the completion of these studies. This work was supported by NIH/NIDCD R01 DC007613, F30DC010522, and NIH/NCRR extramural research facilities construction (C06) grants C06 RR015455 and C06 RR14516 from the National Center for Research Resources, as well as the MUSC GAANN fellowship in Cell and Neurobiology. Imaging facilities for this research were supported by Cancer Center Support Grant P30 CA138313 to the Hollings Cancer Center, Medical University of South Carolina. Additional support for this work was provided by the NIDCD Intramural Research Program (ZIA DC00079).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 165 Ashley Ave, Charleston, SC, 29425, USA

    Tiffany G. Baker, Carlene S. Brandon, Inga K. Kramarenko, Shimon P. Francis, Mona Taleb & Keely M. Marshall

  2. National Institute on Deafness and other Communication Disorders, National Institutes of Health, 35A Convent Drive, Bethesda, MD, 20892, USA

    Soumen Roy & Lisa L. Cunningham

  3. Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

    Reto Schwendener

  4. Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, 165 Ashley Ave, Charleston, SC, 29425, USA

    Fu-Shing Lee

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  1. Tiffany G. Baker
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  2. Soumen Roy
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Correspondence to Lisa L. Cunningham.

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Baker, T.G., Roy, S., Brandon, C.S. et al. Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death. JARO 16, 67–80 (2015). https://doi.org/10.1007/s10162-014-0491-7

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