Cardiotoxicity of sorafenib is mediated through elevation of ROS level and CaMKII activity and dysregulation of calcium homoeostasis

Ma, Wenzhuo; Liu, Mei; Liang, Fanfan; Zhao, Lili; Gao, Chenying; Jiang, Xu; Zhang, Xin; Zhan, Hong; Huang, Hao; Zhao, Zhenghang

doi:10.1111/bcpt.13318

Cited by 47 publications

(24 citation statements)

References 44 publications

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“…Growing evidence suggests that accumulation of Ca 2+ in mitochondria leads to ROS production. 43,44 In the present study, we showed that the forced expression of MCU in CRC cells greatly enhanced mitochondrial Ca 2+ uptake and a markedly increased the production of ROS. Moreover, growing evidence has demonstrated that there is an association between ROS and NF-κB signaling.…”

Section: Discussionsupporting

confidence: 54%

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Yang

Jin

Wang

et al. 2020

Sig Transduct Target Ther

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Mitochondrial calcium uniporter (MCU) has an important role in regulating mitochondrial calcium (Ca 2+) homeostasis. Dysregulation of mitochondrial Ca 2+ homeostasis has been implicated in various cancers. However, it remains unclear whether MCU regulates mitochondrial Ca 2+ uptake to promote cell growth in colorectal cancer (CRC). Therefore, in the present study the expression of MCU in CRC tissues and its clinical significance were examined. Following which, the biological function of MCUmediated mitochondrial Ca 2+ uptake in CRC cell growth and the underlying mechanisms were systematically evaluated using in in vitro and in vivo assays, which included western blotting, cell viability and apoptosis assays, as well as xenograft nude mice models. Our results demonstrated that MCU was markedly upregulated in CRC tissues at both the mRNA and protein levels. Upregulated MCU was associated with poor prognosis in patients with CRC. Our data reported that upregulation of MCU enhanced the mitochondrial Ca 2+ uptake to promote mitochondrial biogenesis, which in turn facilitated CRC cell growth in vitro and in vivo. In terms of the underlying mechanism, it was identified that MCU-mediated mitochondrial Ca 2+ uptake inhibited the phosphorylation of transcription factor A, mitochondrial (TFAM), and thus enhanced its stability to promote mitochondrial biogenesis. Furthermore, our data indicated that increased mitochondrial Ca 2+ uptake led to increased mitochondrial production of ROS via the upregulation of mitochondrial biogenesis, which subsequently activated NF-κB signaling to accelerate CRC growth. In conclusion, the results indicated that MCU-induced mitochondrial Ca 2+ uptake promotes mitochondrial biogenesis by suppressing phosphorylation of TFAM, thus contributing to CRC cell growth. Our findings reveal a novel mechanism underlying mitochondrial Ca 2+-mediated CRC cell growth and may provide a potential pharmacological target for CRC treatment.

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Section: Discussionsupporting

confidence: 54%

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Yang

Jin

Wang

et al. 2020

Sig Transduct Target Ther

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“…Accordingly, we found that the inhibition of CI-, CII-, and CIII-linked respiration started at 5 µM, whereas mitochondrial ROS accumulation and activation of caspase 3/7 started at 50 µM. Our data confirm recently published results showing increased mitochondrial ROS in isolated rat ventricular myocytes [34]. However, a previous study of human cardiomyocytes demonstrated an increase in ROS at the cellular but not at the mitochondrial level [35].…”

Section: Discussionsupporting

confidence: 91%

Mitochondrial Toxicity Associated with Imatinib and Sorafenib in Isolated Rat Heart Fibers and the Cardiomyoblast H9c2 Cell Line

Bouitbir

Panajatovic

Krähenbühl

2022

IJMS

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Tyrosine kinase inhibitors (TKIs) are associated with cardiac toxicity, which may be caused by mitochondrial toxicity. The underlying mechanisms are currently unclear and require further investigation. In the present study, we aimed to investigate in more detail the role of the enzyme complexes of the electron transfer system (ETS), mitochondrial oxidative stress, and mechanisms of cell death in cardiac toxicity associated with imatinib and sorafenib. Cardiac myoblast H9c2 cells were exposed to imatinib and sorafenib (1 to 100 µM) for 24 h. Permeabilized rat cardiac fibers were treated with both drugs for 15 min. H9c2 cells exposed to sorafenib for 24 h showed a higher membrane toxicity and ATP depletion in the presence of galactose (favoring mitochondrial metabolism) compared to glucose (favoring glycolysis) but not when exposed to imatinib. Both TKIs resulted in a higher dissipation of the mitochondrial membrane potential in galactose compared to glucose media. Imatinib inhibited Complex I (CI)- and CIII- linked respiration under both conditions. Sorafenib impaired CI-, CII-, and CIII-linked respiration in H9c2 cells cultured with glucose, whereas it inhibited all ETS complexes with galactose. In permeabilized rat cardiac myofibers, acute exposure to imatinib and sorafenib decreased CI- and CIV-linked respiration in the presence of the drugs. Electron microscopy showed enlarged mitochondria with disorganized cristae. In addition, both TKIs caused mitochondrial superoxide accumulation and decreased the cellular GSH pool. Both TKIs induced caspase 3/7 activation, suggesting apoptosis as a mechanism of cell death. Imatinib and sorafenib impaired the function of cardiac mitochondria in isolated rat cardiac fibers and in H9c2 cells at plasma concentrations reached in humans. Both imatinib and sorafenib impaired the function of enzyme complexes of the ETS, which was associated with mitochondrial ROS accumulation and cell death by apoptosis.

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“…The occurrence of necroptosis is related to MLKL phosphorylation by RIP3 [ 129 ]. In addition, the downstream factor of RIP3, calcium/calmodulin-dependent protein kinase II, increases ROS levels to induce mitochondrial dysfunction [ 130 ]. Phosphorylation of RIP3 and MLKL activates phosphoglycerate mutase family member 5 (PGAM5) and then induces necroptosis [ 131 , 132 ] in collaboration with dynamin-related protein 1 (Drp1) which is a dynamics-related protein that mediates mitochondrial fission, fusion, and mitophagy [ 133 ].…”

Section: Necroptosismentioning

confidence: 99%

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

Zhou

Liao

Mei

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. Necroptosis, an alternative form of programmed necrosis, is regulated by receptor-interacting protein (RIP) 1 activation and by RIP3 and mixed-lineage kinase domain-like (MLKL) phosphorylation. Ferroptosis and necroptosis both play important roles in the pathological progress in ischemic stroke, which is a complex brain disease regulated by several cell death pathways. In the past few years, increasing evidence has suggested that the crosstalk occurs between necroptosis and ferroptosis in ischemic stroke. However, the potential links between ferroptosis and necroptosis in ischemic stroke have not been elucidated yet. Hence, in this review, we overview and analyze the mechanism underlying the crosstalk between necroptosis and ferroptosis in ischemic stroke. And we find that iron overload, one mechanism of ferroptosis, leads to mitochondrial permeability transition pore (MPTP) opening, which aggravates RIP1 phosphorylation and contributes to necroptosis. In addition, heat shock protein 90 (HSP90) induces necroptosis and ferroptosis by promoting RIP1 phosphorylation and suppressing glutathione peroxidase 4 (GPX4) activation. In this work, we try to deliver a new perspective in the exploration of novel therapeutic targets for the treatment of ischemic stroke.

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Cardiotoxicity of sorafenib is mediated through elevation of ROS level and CaMKII activity and dysregulation of calcium homoeostasis

Cited by 47 publications

References 44 publications

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Mitochondrial Toxicity Associated with Imatinib and Sorafenib in Isolated Rat Heart Fibers and the Cardiomyoblast H9c2 Cell Line

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

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