Journal article
Atypical G Protein beta 5 Promotes Cardiac Oxidative Stress, Apoptosis, and Fibrotic Remodeling in Response to Multiple Cancer Chemotherapeutics
Cancer research (Chicago, Ill.), Vol.78(2), pp.528-541
01/15/2018
DOI: 10.1158/0008-5472.CAN-17-1280
PMID: 29141899
Abstract
The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. Though distinct in their mechanisms of action, doxorubicin, paclitaxel, and 5-FU all induce rapid and robust upregulation of atypical G protein G beta(5) in the myocardium correlating with oxidative stress, myocyte apoptosis, and the accumulation of proinflammatory and profibrotic cytokines. In ventricular cardiac myocytes (VCM), G beta(5) deficiency provided substantial protection against the cytotoxic actions of chemotherapeutics, including reductions in oxidative stress and simultaneous attenuation of ROS-dependent activation of the ATM and CaMKII proapoptotic signaling cascades. In addition, G beta(5) loss allowed for maintenance of Delta psi m, basal mitochondrial calcium uniporter expression, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation-contraction coupling. The deleterious effects of G beta(5) are not restricted to VCM, however, as G beta(5) knockdown also reduces chemotherapy-induced release of proinflammatory cytokines (e.g., TNF alpha), hypertrophic factors (e.g., ANP), and profibrotic factors (e.g., TGF beta 1) from both VCM and ventricular cardiac fibroblasts, with the most dramatic reduction occurring in cocultured cells. Our experiments suggest that G beta(5) facilitates the myofibroblast transition, the persistence of which contributes to pathologic remodeling and heart failure. The convergence of G beta(5)-mediated, ROS-dependent signaling pathways in both cell types represents a critical etiological factor in the pathogenesis of chemotherapy-induced cardiotoxicity. Indeed, intracardiac injection of G beta(5)-targeted shRNA allowed for heart-specific protection against the damaging impact of chronic chemotherapy. Together, our results suggest that inhibition of G beta(5) might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.
Significance: These findings suggest that inhibiting an atypical G-protein might provide a strategy to limit the cardiotoxicity in cancer patients treated with anthracyclines, taxanes, or fluoropyrimidines. (C) 2017 AACR.
Details
- Title: Subtitle
- Atypical G Protein beta 5 Promotes Cardiac Oxidative Stress, Apoptosis, and Fibrotic Remodeling in Response to Multiple Cancer Chemotherapeutics
- Creators
- Sreemoyee Chakraborti - Sanjay Gandhi Post Graduate Institute of Medical SciencesArnab Pramanick - Sanjay Gandhi Post Graduate Institute of Medical SciencesSudipta Saha - Babasaheb Bhimrao Ambedkar UniversitySomnath Singha Roy - Sanjay Gandhi Postgrad Inst Med Sci, Ctr Biomed Res, Lucknow, Uttar Pradesh, IndiaArnab Ray Chaudhuri - Erasmus University RotterdamMadhusudan Das - University of CalcuttaSujoy Ghosh - University of CalcuttaAdele Stewart - Florida Atlantic UniversityBiswanath Maity - Centre of Biomedical Research
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.78(2), pp.528-541
- DOI
- 10.1158/0008-5472.CAN-17-1280
- PMID
- 29141899
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 14
- Grant note
- BT/RLF/Re-entry/15/2013 / Ramalingaswami Fellowship, Department of Biotechnology EMR/2016/006873 / Department of Science and Technology, SERB, Government of India
- Language
- English
- Date published
- 01/15/2018
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618644302771
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