Atypical G Protein β5 Promotes Cardiac Oxidative Stress, Apoptosis, and Fibrotic Remodeling in Response to Multiple Cancer Chemotherapeutics.
TL;DR: The experiments suggest that inhibition of Gβ5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.
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 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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TL;DR: In this paper, the authors identify G protein β5 (Gβ5), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver.
Abstract: Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe hepatotoxicity. Here we identify G protein β5 (Gβ5), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver. Liver-specific knockdown of Gβ5 in mice protected the liver from APAP-dependent fibrosis, cell loss, oxidative stress, and inflammation following either acute or chronic APAP administration. Conversely, overexpression of Gβ5 in liver was sufficient to drive hepatocyte dysfunction and loss. In hepatocytes, Gβ5 depletion ameliorated mitochondrial dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced cell death. Further, Gβ5 knockdown also reversed impacts of APAP on kinase cascades (e.g. ATM/AMPK) signaling to mammalian target of rapamycin (mTOR), a master regulator of autophagy and, as a result, interrupted autophagic flux. Though canonically relegated to nuclear DNA repair pathways, ATM also functions in the cytoplasm to control cell death and autophagy. Indeed, we now show that Gβ5 forms a direct, stable complex with the FAT domain of ATM, important for autophosphorylation-dependent kinase activation. These data provide a viable explanation for these novel, G protein-independent actions of Gβ5 in liver. Thus, Gβ5 sits at a critical nexus in multiple pathological sequelae driving APAP-dependent liver damage.
5 citations
20 Sep 2021
5 citations
TL;DR: Dimethyl itaconate (DI) has been reported to be efficacious in colorectal cancer by decreasing IL-1β release from intestinal epithelial cells as discussed by the authors .
Abstract: Hepatocellular carcinoma (HCC) is one of the most common tumors affecting a large population worldwide, with the fifth and seventh greatest mortality rates among men and women, respectively, and the third prime cause of mortality among cancer victims. Dimethyl itaconate (DI) has been reported to be efficacious in colorectal cancer by decreasing IL-1β release from intestinal epithelial cells. In this study, diethylnitrosamine (DEN)-induced HCC in male albino Wistar rats was treated with DI as an anticancer drug. The function and molecular mechanism of DI against HCC in vivo were assessed using histopathology, enzyme-linked immunosorbent assay (ELISA), and Western blot studies. Metabolomics using 1H-NMR was used to investigate metabolic profiles. As per molecular insights, DI has the ability to trigger mitochondrial apoptosis through iNOS- and eNOS-induced activation of the NF-κB/Bcl-2 family of proteins, CytC, caspase-3, and caspase-9 signaling cascade. Serum metabolomics investigations using 1H-NMR revealed that aberrant metabolites in DEN-induced HCC rats were restored to normal following DI therapy. Furthermore, our data revealed that the DI worked as an anti-HCC agent. The anticancer activity of DI was shown to be equivalent to that of the commercial chemotherapeutic drug 5-fluorouracil.
3 citations
TL;DR: In this article , the role of non-cardiomyocytes in anticancer drug-induced cardiotoxicity was discussed, including the mechanism of direct damage to resident noncardiocyte, cardiomyocyte injury caused by paracrine modality, myocardial inflammation induced by transient cell populations and the protective agents that focused on noncardioromyocytes.
2 citations
TL;DR: In this article, the authors identify RGS7, upregulated in cardiac cells following chemotherapy exposure, as a key driver of chemotherapy-dependent oxidative stress, cell loss, and fibrosis in heart.
Abstract: Significance Despite decades of clinical use, the utility of cancer chemotherapeutics is limited by adverse cardiac events. Although progress has been made in elucidating mechanisms underlying the pathogenesis of chemotherapy-dependent cardiotoxicity, the highly diverse rate of disease progression and lack of biomarkers have stymied efforts to prevent or reverse cardiac damage. Here, we identify RGS7, up-regulated in cardiac cells following chemotherapy exposure, as a key driver of chemotherapy-dependent oxidative stress, cell loss, and fibrosis in heart. Importantly, while RGS7 is both necessary and sufficient to drive chemotherapy-dependent heart damage, modulation of RGS7 expression in cancer cells fails to impact their sensitivity to chemotherapeutic drugs. Thus, RGS7 emerges as a potential therapeutic target in the detection or mitigation of chemotherapy-associated cardiac damage.
2 citations
References
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TL;DR: Fixed-time assay measuring H 2 O 2 consumption and continuous monitoring of Glutathione disulfide (GSSG) formation are cited here.
Abstract: Publisher Summary To determine glutathione peroxidase reliably, some factors of potential pitfall have to be considered, for example, enzymatic side reactions of substrates (especially when crude tissue samples are assayed), high and variable spontaneous reaction rates of substrates, and the peculiar kinetics of the enzyme itself. With the best documented example, the enzyme of bovine red blood cells, ping-pong kinetics with infinite limiting maximum velocities, and Michaelis constants have been established. This means that the generally recommended conditions for determination of enzyme activity––that is, “saturating” concentrations of all substrates, cannot possibly be fulfilled. In consequence, compromises are inevitable in the choice of substrate concentration for the assay and in the definition of the unit of activity. Fixed-time assay measuring H 2 O 2 consumption and continuous monitoring of Glutathione disulfide (GSSG) formation are cited here. The main differences between the assay procedure described and those proposed by others are listed in the chapter. To compare the results obtained by different procedures, appropriate empirical converting factors are also given.
4,341 citations
"Atypical G Protein β5 Promotes Card..." refers methods in this paper
...GPX activity was measured using the method of Flohe and Gunzler(30)....
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TL;DR: An overview of issues confirms that anthracyclines remain “evergreen” drugs with broad clinical indications but have still an improvable therapeutic index.
Abstract: The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.
3,320 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Gβ5 promotes chemotherapeutic-induced activation of DNA damage signaling– Multiple apoptotic signaling cascades are believed to mediate ROS-induced cardiac damage including the ATM/p53 pathway(32)....
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TL;DR: A critical analysis of the challenges and limitations of the most widely used fluorescent probes for detecting and measuring reactive oxygen and nitrogen species and proposed guidelines that will help present and future researchers with regard to the optimal use of selected fluorescent probes and interpretation of results are presented.
1,423 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Because there are several limitations to the use of CM-H2DCFDA fluorescent probes in detecting total ROS from cells or tissue(31), amongst them an inability to differentiate between the various reactive species, we extended our analysis of Gβ5-dependent ROS generation to include direct measurement of H2O2....
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TL;DR: It is shown that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM and highlights the critical importance of oxidation-dependent CaMK II activation to AngII and ischemic myocardial apoptosis.
989 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...The pro-apoptotic actions of ATM and CaMKII following chemotherapy exposure require Gβ5and ROS– Based on the recent emergence of oxidative mechanisms of activation for both CaMKII(35) and ATM(36), we suspected that the ability of Gβ5 to promote activation of both kinases required Gβ5-dependent ROS generation....
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...Because it was recently discovered that CaMKII can be directly activated by oxidation of the enzyme’s regulatory domain(35), we hypothesized that the link between Gβ5 and mitochondria might lie in ROS-dependent CaMKII activation....
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TL;DR: It is shown that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex, and that ATM is an important sensor of reactive oxygen species in human cells.
Abstract: The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
955 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...The pro-apoptotic actions of ATM and CaMKII following chemotherapy exposure require Gβ5and ROS– Based on the recent emergence of oxidative mechanisms of activation for both CaMKII(35) and ATM(36), we suspected that the ability of Gβ5 to promote activation of both kinases required Gβ5-dependent ROS generation....
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