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Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes
- Source :
- Molecular Cancer Therapeutics. 15:1321-1331
- Publication Year :
- 2016
- Publisher :
- American Association for Cancer Research (AACR), 2016.
-
Abstract
- Dysregulation of autophagy has been implicated in various cardiovascular diseases. Trastuzumab, a humanized monoclonal antibody, binds to HER2 domain IV and is approved for the treatment of HER2-positive breast cancer. Trastuzumab therapy is associated with considerable cardiotoxicity, the mechanism of which remains unclear. HER2 signaling plays a pivotal role in cardiomyocyte development and survival and is essential for the prevention of cardiomyopathy. However, a direct link has not been confirmed between trastuzumab-induced cardiomyopathy and impaired HER2 signaling. Our data reveal a novel mechanism by which trastuzumab dysregulates HER2 signaling and impairs basal autophagic process in human primary cardiomyocytes. Specifically, trastuzumab treatment leads to the phosphorylation of HER1-Y845 and HER2-Y1248 and the activation of Erk. This in turn results in upregulation of mTOR signaling pathway and subsequently inhibition of autophagy in primary cardiomyocytes and C57BL/6 mice. Trastuzumab-induced downregulation of autophagy is further supported by the fact that trastuzumab treatment reduces protein levels of autophagosome-associated signaling molecules such as Atg 5-12, Atg 7, Atg 14, and Beclin 1. We further demonstrated that trastuzumab-mediated inhibition of autophagy resulted in the increased production of reactive oxygen species (ROS) in cardiomyocytes. Pertuzumab, another anti-HER2 therapeutic mAb binding to HER2 domain II, fails to modulate HER2 signaling and is unable to inhibit autophagy and to increase ROS production in cardiomyocytes. This study provides novel mechanistic insights into trastuzumab-induced cardiotoxicity, which may assist in formulating novel approaches for clinical management of trastuzumab-induced cardiomyopathy. Mol Cancer Ther; 15(6); 1321–31. ©2016 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Cell signaling
MAP Kinase Signaling System
Receptor, ErbB-2
Down-Regulation
Pharmacology
Biology
Antibodies, Monoclonal, Humanized
Mice
03 medical and health sciences
Downregulation and upregulation
Trastuzumab
Autophagy
medicine
Animals
Humans
Myocytes, Cardiac
Phosphorylation
skin and connective tissue diseases
neoplasms
Cells, Cultured
chemistry.chemical_classification
Cardiotoxicity
Reactive oxygen species
ErbB Receptors
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
030104 developmental biology
Oncology
chemistry
Cancer research
Pertuzumab
Reactive Oxygen Species
medicine.drug
Subjects
Details
- ISSN :
- 15388514 and 15357163
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Therapeutics
- Accession number :
- edsair.doi.dedup.....781e283adf9d00ae8d95fa2a4836b2b9