Upregulation of IGF-IIRα intensifies doxorubicin-induced cardiac damage

Sudhir Pandey, Wei Wen Kuo, Tsung Jung Ho, Yu Lan Yeh, Chia Yao Shen, Ray Jade Chen, Ruey Lin Chang, Pei Ying Pai, V. Vijaya Padma, Chih Yang Huang, Chih Yang Huang

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Abstract

Cardiotoxicity by doxorubicin hampers its therapeutic potential as an anticancer drug, but mechanisms leading to cardiotoxicity remain contentious. Through this study, the functional contribution of insulin-like growth factor receptor type II α (IGF-IIRα) which is a novel stress-inducible protein was explored in doxorubicin-induced cardiac stress. Employing both in vitro H9c2 cells and in vivo transgenic rat models (SD-TG [IGF-IIRα]) overexpressing IGF-IIRα specifically in heart, we found that IGF-IIRα leads to cardiac structural abnormalities and functional perturbations that were severely aggravated by doxorubicin-induced cardiac stress. Overexpression of IGF-IIRα leads to cumulative elevation of stress associated cardiac hypertrophy and apoptosis factors. There was a significant reduction of survival associated proteins p-Akt and estrogen receptor β/α, and abnormal elevation of cardiac hypertrophy markers such as atrial natriuretic peptide, cardiac troponin-I, and apoptosis-inducing agents such as p53, Bax, and cytochrome C, respectively. IGF-IIRα also altered the expressions of AT1R, ERK1/2, and p38 proteins. Besides, IGF-IIRα also increased the reactive oxygen species production in H9c2 cells which were markedly aggravated by doxorubicin treatment. Together, we showed that IGF-IIRα is a novel stress-induced protein that perturbed cardiac homeostasis and cumulatively exacerbated the doxorubicin-induced cardiac injury that perturbed heart functions and ensuing cardiomyopathy.

Original languageEnglish
Pages (from-to)16956-16966
Number of pages11
JournalJournal of Cellular Biochemistry
Volume120
Issue number10
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • Bax
  • cardiotoxicity
  • doxorubicin
  • IGF-IIRα
  • p53
  • transgenic rats

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Pandey, S., Kuo, W. W., Ho, T. J., Yeh, Y. L., Shen, C. Y., Chen, R. J., Chang, R. L., Pai, P. Y., Padma, V. V., Huang, C. Y., & Huang, C. Y. (2019). Upregulation of IGF-IIRα intensifies doxorubicin-induced cardiac damage. Journal of Cellular Biochemistry, 120(10), 16956-16966. https://doi.org/10.1002/jcb.28957