American Association for Cancer Research
00085472can171280-sup-182680_3_supp_4384597_pz7m6t.pptx (351.4 kB)

Supplementary Figure 3 from Atypical G Protein β5 Promotes Cardiac Oxidative Stress, Apoptosis, and Fibrotic Remodeling in Response to Multiple Cancer Chemotherapeutics

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posted on 2023-03-31, 01:29 authored by Sreemoyee Chakraborti, Arnab Pramanick, Sudipta Saha, Somnath Singha Roy, Arnab Ray Chaudhuri, Madhusudan Das, Sujoy Ghosh, Adele Stewart, Biswanath Maity

Figure S3. Gβ5 promotes chemotherapeutic drug-induced oxidative stress in isolated VCM.



Department of Biotechnology and Department of Science and Technology

Ramalingaswami Fellowship

Department of Biotechnology, and Department of Science and Technology



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 Gβ5 in the myocardium correlating with oxidative stress, myocyte apoptosis, and the accumulation of proinflammatory and profibrotic cytokines. In ventricular cardiac myocytes (VCM), Gβ5 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, Gβ5 loss allowed for maintenance of Δψm, basal mitochondrial calcium uniporter expression, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation–contraction coupling. The deleterious effects of Gβ5 are not restricted to VCM, however, as Gβ5 knockdown also reduces chemotherapy-induced release of proinflammatory cytokines (e.g., TNFα), hypertrophic factors (e.g., ANP), and profibrotic factors (e.g., TGFβ1) from both VCM and ventricular cardiac fibroblasts, with the most dramatic reduction occurring in cocultured cells. Our experiments suggest that Gβ5 facilitates the myofibroblast transition, the persistence of which contributes to pathologic remodeling and heart failure. The convergence of Gβ5-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 Gβ5-targeted shRNA allowed for heart-specific protection against the damaging impact of chronic chemotherapy. Together, our results suggest that inhibition of Gβ5 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. Cancer Res; 78(2); 528–41. ©2017 AACR.

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