Heat shock protein 90 and ErbB2 in the cardiac response to doxorubicin injury

Kathleen Gabrielson*, Djahida Bedja, Scott Pin, Allison Tsao, Lucio Gama, Bibo Yuan, Nicole Muratore

*Corresponding author for this work

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

A major drawback to doxorubicin as a cancer-treating drug is cardiac toxicity. To understand the mechanism of doxorubicin cardiac toxicity and the potent synergic effect seen when doxorubicin is combined with anti-ErbB2 (trastuzumab), we developed an in vivo rat model that exhibits progressive dose-dependent cardiac damage and loss of cardiac function after doxorubicin treatment. The hearts of these animals respond to doxorubicin damage by increasing levels of ErbB2 and the ErbB family ligand, neuregulin 1β, and by activating the downstream Akt signaling pathway. These increases in ErbB2 protein levels are not due to increased ErbB2 mRNA, however, suggesting post-transcriptional mechanisms for regulating this protein in the heart. Accordingly, levels of heat shock protein 90 (HSP90), a known ErbB2 protein stabilizer and chaperone, are increased by doxorubicin treatment, and coimmunoprecipitation reveals binding of HSP90 to ErbB2. Isolated cardiomyocytes are more susceptible to doxorubicin after treatment with HSP90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin, suggesting that the HSP90 is protective during doxorubicin treatment. Thus, our results provide one plausible mechanism for the susceptibility of the heart to anti-ErbB2 therapy post-doxorubicin therapy in subclinical and clinical conditions. Additionally, these results suggest that further testing is needed for HSP90 inhibitors under various conditions in the heart.

Original languageEnglish
Pages (from-to)1436-1441
Number of pages6
JournalCancer Research
Volume67
Issue number4
DOIs
Publication statusPublished - 15 Feb 2007
Externally publishedYes

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    Gabrielson, K., Bedja, D., Pin, S., Tsao, A., Gama, L., Yuan, B., & Muratore, N. (2007). Heat shock protein 90 and ErbB2 in the cardiac response to doxorubicin injury. Cancer Research, 67(4), 1436-1441. https://doi.org/10.1158/0008-5472.CAN-06-3721