Study of ER stress and apoptotic proteins in the heart and tumor exposed to doxorubicin

Bagchi, Ashim K.; Malik, Akshi; Akolkar, Gauri; Zimmer, Alexsandra; Belló‐Klein, Adriane; Angelis, Kátia De; Jassal, Davinder S.; Fini, Mehdi A.; Stenmark, Kurt R.; Singal, Pawan K.

doi:10.1016/j.bbamcr.2021.119039

Cited by 24 publications

(32 citation statements)

References 45 publications

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“…We have recently reported that Dox-induced ER stress in cardiomyocytes is a delayed response of the Bax-mediated cell death process [ 20 ]. We now show that this delayed ER stress-mediated cell death pathway may be determined by iNOS-regulated inflammation during DIC.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, NO produced from iNOS can be an activator of ER stress pathways controlled by mitochondrial p53 independently. Dox-induced adaptive responses attenuate ER stress in cancer cells [ 20 ]; however, its delayed effect in cardiomyocyte ER stress is not completely understood.…”

Section: Discussionmentioning

confidence: 99%

“…Both iNOS-dependent and -independent pathways are mediated by OS-induced ER stress [ 21 ]. A potential role for ER stress in Dox-induced cardiotoxicity has been demonstrated by us and others [ 20 , 22 ]. Dox increases proinflammatory cytokines [ 6 , 7 ], which may have an important role in UPR signaling, possibly via iNOS activation and increased NO generation.…”

Section: Introductionmentioning

confidence: 87%

“…Approximately 5–6 µm paraffin-embedded heart tissue sections were cut and mounted on microscopic slides, de-paraffinized in xylene and hydrated through graded series of alcohol as described earlier [ 20 ]. Tissue sections were permeabilized in 0.05% triton-X100 for 15 min at RT.…”

Section: Methodsmentioning

confidence: 99%

“…Bip is one of the most important chaperones in UPR regulation [ 17 ] which triggers cellular apoptotic pathways to remove cells under ER stress [ 18 , 19 ]. Recently, we have shown that Dox promoted UPR-related apoptotic protein CCAAT/enhancer-binding homologous protein (CHOP)/DNA damage-inducible transcript 3 (DDIT3) in normal as well as in hearts from tumor-bearing animals which was dependent on Bax—a mitochondrial proapoptotic protein [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Stress Promotes iNOS/NO and Influences Inflammation in the Development of Doxorubicin-Induced Cardiomyopathy

Bagchi

Malik

Akolkar³

et al. 2021

Antioxidants

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Doxorubicin (Dox) is known to cause heart failure in some cancer patients. Despite extensive studies over the past half century, the subcellular basis of Dox-induced cardiomyopathy (DIC) is still elusive. Earlier, we suggested that Dox causes a delayed activation of unfolded protein response (UPR) which may promote mitochondrial Bax activity leading to cardiomyocyte death. As a follow up, using NO donor, S-Nitroso-N-acetyl-d,l-penicillamine (SNAP), and/or NOS inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), we now show that endoplasmic reticulum (ER) stress promotes inflammation through iNOS/NO-induced TLR2 activation. In vivo Dox treatment increased mitochondrial iNOS to promote ER stress as there was an increase in Bip (Grp78) response, proapoptotic CHOP (DDIT3) and ER-mediated Caspase 12 activation. Increased iNOS activity is associated with an increase in TLR2 and TNF-α receptor associated factor 2 (TRAF2). These two together with NF-κB p105/50 expression and a synergistic support through ER stress, promote inflammatory response in the myocardium leading to cell death and ultimately fostering DIC conditions. In the presence of NOS inhibitor, such detrimental effects of Dox were inhibited, suggesting iNOS/NO as key mediators of Dox-induced inflammatory as well as apoptotic responses.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Endoplasmic Reticulum Stress Promotes iNOS/NO and Influences Inflammation in the Development of Doxorubicin-Induced Cardiomyopathy

Bagchi

Malik

Akolkar³

et al. 2021

Antioxidants

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DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis

et al. 2022

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The acidic, hypoxic and nutrient-deprived tumor microenvironment may induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) may exert an important cytoprotective role by promoting folding of newly synthesized proteins and cancer cell survival. The lack of DNMT2/TRDMT1 methyltransferase-mediated C38 tRNA methylation compromises translational fidelity that may result in the accumulation of misfolded and aggregated proteins leading to proteotoxic stress-related cell death. In the present study, DNMT2/TRDMT1 gene knockout-mediated effects were investigated during doxorubicin (DOX)-induced ER stress and PERK-, IRE1- and ATF6-orchestrated UPR in four genetically different cellular models of cancer (breast and cervical cancer, osteosarcoma and glioblastoma cells). Upon DOX stimulation, DNMT2/TRDMT1 gene knockout impaired PERK activation and modulated NSUN and 5-methylcytosine RNA-based responses and microRNA profiles. The lack of DNMT2/TRDMT1 gene in DOX-treated four cancer cell lines resulted in decreased levels of four microRNAs, namely, miR-23a-3p, miR-93-5p, miR-125a-5p and miR-191-5p involved in the regulation of several pathways such as ubiquitin-mediated proteolysis, amino acid degradation and translational misregulation in cancer. We conclude that DNMT2/TRDMT1 gene knockout, at least in selected cellular cancer models, affects adaptive responses associated with protein homeostasis networks that during prolonged ER stress may result in increased sensitivity to apoptotic cell death.

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Mandatory role of endoplasmic reticulum and its pentose phosphate shunt in the myocardial defense mechanisms against the redox stress induced by anthracyclines

Sambuceti,

Cossu,

Vitale

et al. 2023

Mol Cell Biochem

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Anthracyclines’ cardiotoxicity involves an accelerated generation of reactive oxygen species. This oxidative damage has been found to accelerate the expression of hexose-6P-dehydrogenase (H6PD), that channels glucose-6-phosphate (G6P) through the pentose phosphate pathway (PPP) confined within the endoplasmic/sarcoplasmic reticulum (SR). To verify the role of SR-PPP in the defense mechanisms activated by doxorubicin (DXR) in cardiomyocytes, we tested the effect of this drug in H6PD knockout mice (H6PD−/−). Twenty-eight wildtype (WT) and 32 H6PD−/− mice were divided into four groups to be treated with intraperitoneal administration of saline (untreated) or DXR (8 mg/Kg once a week for 3 weeks). One week thereafter, survivors underwent imaging of 18F-deoxyglucose (FDG) uptake and were sacrificed to evaluate the levels of H6PD, glucose-6P-dehydrogenase (G6PD), G6P transporter (G6PT), and malondialdehyde. The mRNA levels of SR Ca2+-ATPase 2 (Serca2) and ryanodine receptors 2 (RyR2) were evaluated and complemented with Hematoxylin/Eosin staining and transmission electron microscopy. During the treatment period, 1/14 DXR-WT and 12/18 DXR-H6PD−/− died. At microPET, DXR-H6PD−/− survivors displayed an increase in left ventricular size (p < 0.001) coupled with a decreased urinary output, suggesting a severe hemodynamic impairment. At ex vivo analysis, H6PD−/− condition was associated with an oxidative damage independent of treatment type. DXR increased H6PD expression only in WT mice, while G6PT abundance increased in both groups, mismatching a generalized decrease of G6PD levels. Switching-off SR-PPP impaired reticular accumulation of Ca2+ decelerating Serca2 expression and upregulating RyR2 mRNA level. It thus altered mitochondrial ultrastructure eventually resulting in a cardiomyocyte loss. The recognized vulnerability of SR to the anthracycline oxidative damage is counterbalanced by an acceleration of G6P flux through a PPP confined within the reticular lumen. The interplay of SR-PPP with the intracellular Ca2+ exchanges regulators in cardiomyocytes configure the reticular PPP as a potential new target for strategies aimed to decrease anthracycline toxicity.

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Study of ER stress and apoptotic proteins in the heart and tumor exposed to doxorubicin

Cited by 24 publications

References 45 publications

Endoplasmic Reticulum Stress Promotes iNOS/NO and Influences Inflammation in the Development of Doxorubicin-Induced Cardiomyopathy

Endoplasmic Reticulum Stress Promotes iNOS/NO and Influences Inflammation in the Development of Doxorubicin-Induced Cardiomyopathy

DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis

Mandatory role of endoplasmic reticulum and its pentose phosphate shunt in the myocardial defense mechanisms against the redox stress induced by anthracyclines

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