A model for cardiomyocyte cell death: Insights into mechanisms of oncosis

Weerasinghe, Priya; Hallock, Sarathi; Brown, Robert E.; Loose, David S.; Buja, L. Maximilian

doi:10.1016/j.yexmp.2012.04.022

Cited by 27 publications

(22 citation statements)

References 27 publications

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“…Microarray analysis on RNAs prepared from cultured mouse cardiomyocytes using Illumina Beadchips reinforced earlier observations of genetic and transcriptional involvement in oncosis (Weerasinghe et al, 2012). Sanguinarine, at oncosis-inducing higher concentrations altered the expression of 2514 probes, and at the lower apoptosisinducing concentrations altered the expression of 1643 probes at a level of significance of p b 0.001 (Fig.…”

Section: Sanguinarine (Anticancer Agent)-induced Bimodal Cell Deathsupporting

confidence: 77%

“…Studies utilizing caspase inhibitors and mutant mouse models indicate that treated or mutant animals subjected to myocardial ischemia have reduced the extent of infarction, but not complete protection, suggesting that the mechanism of cell injury and death in early myocardial ischemia involves both oncosis and apoptosis in approximately equal degree (Buja and Vela, 2008;Buja and Weerasinghe, 2010;Foo et al, 2005). As discussed above, our studies have shown that cardiomyocytes have the molecular machinery to progress to cell death by oncosis and apoptosis (Weerasinghe et al, 2012). The rate and magnitude of ATP depletion appear to be an important influence on progression of cell damage via oncosis in the setting of rapid ATP depletion or apoptosis in the setting of partial ATP preservation.…”

Section: Myocardial Ischemic Injury and Infarctionmentioning

confidence: 53%

“…These findings corroborate active cellular functioning at the higher dose including the activation of major canonical pathways. More exciting were the findings that in oncosis some of the inductions such as perforin, a cytolytic protein found in the granules of CD8 T-cells and NK cells, are induced more than 11-fold (Weerasinghe et al, 2012).…”

Section: Sanguinarine (Anticancer Agent)-induced Bimodal Cell Deathmentioning

confidence: 99%

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Oncosis: An important non-apoptotic mode of cell death

Weerasinghe

Buja

2012

Experimental and Molecular Pathology

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Section: Sanguinarine (Anticancer Agent)-induced Bimodal Cell Deathsupporting

confidence: 77%

Section: Myocardial Ischemic Injury and Infarctionmentioning

confidence: 53%

Section: Sanguinarine (Anticancer Agent)-induced Bimodal Cell Deathmentioning

confidence: 99%

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Oncosis: An important non-apoptotic mode of cell death

Weerasinghe

Buja

2012

Experimental and Molecular Pathology

Self Cite

194

182

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“…At the present time, there are limited data on molecular markers of oncosis in cancer cells. Gene expression profiling of oncotic and apoptotic cardiomyocytes revealed that over-expression of perforin was associated with oncosis (Weerasinghe et al 2013). In our study, treatment with metformin was associated with induction of perforin in FTC133 as well as in BCPAP cells cultured in low-glucose medium.…”

Section: Discussionsupporting

confidence: 55%

Glucose-deprivation increases thyroid cancer cells sensitivity to metformin

Bikas¹,

Jensen²,

Patel³

et al. 2015

Endocrine-Related Cancer

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Metformin inhibits thyroid cancer cell growth. We sought to determine if variable glucose concentrations in medium alter the anti-cancer efficacy of metformin. Thyroid cancer cells (FTC133 and BCPAP) were cultured in high-glucose (20 mM) and low-glucose (5 mM) medium before treatment with metformin. Cell viability and apoptosis assays were performed. Expression of glycolytic genes was examined by real-time PCR, western blot, and immunostaining. Metformin inhibited cellular proliferation in high-glucose medium and induced cell death in low-glucose medium. In low-, but not in high-glucose medium, metformin induced endoplasmic reticulum stress, autophagy, and oncosis. At micromolar concentrations, metformin induced phosphorylation of AMP-activated protein kinase and blocked p-pS6 in low-glucose medium. Metformin increased the rate of glucose consumption from the medium and prompted medium acidification. Medium supplementation with glucose reversed metformin-inducible morphological changes. Treatment with an inhibitor of glycolysis (2-deoxy-D-glucose (2-DG)) increased thyroid cancer cell sensitivity to metformin. The combination of 2-DG with metformin led to cell death. Thyroid cancer cell lines were characterized by over-expression of glycolytic genes, and metformin decreased the protein level of pyruvate kinase muscle 2 (PKM2). PKM2 expression was detected in recurrent thyroid cancer tissue samples.In conclusion, we have demonstrated that the glucose concentration in the cellular milieu is a factor modulating metformin's anti-cancer activity. These data suggest that the combination of metformin with inhibitors of glycolysis could represent a new strategy for the treatment of thyroid cancer.

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“…Preliminary pre-clinical in vitro and in vivo studies have demonstrated that sanguinarine causes apoptosis in human cancer cells [24][25][26][27][28][29]. Recently, sanguinarine was identified as inhibiting the dephosphorylation of casein by human PP2Cα with an IC50 value of 2.5 µM [23], although the inhibitory mechanism is unknown.…”

Section: Inhibition Effects Of Nine Chemicals On Tppha Activitymentioning

confidence: 99%

Structural and Biochemical Characterization of a Cyanobacterial PP2C Phosphatase Reveals Insights into Catalytic Mechanism and Substrate Recognition

Yuan

Wang

et al. 2016

Catalysts

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PP2C-type phosphatases play roles in signal transduction pathways related to abiotic stress. The cyanobacterial PP2C-type phosphatase tPphA specifically dephosphorylates the PII protein, which is a key regulator in cyanobacteria adapting to nitrogen-deficient environments. Previous studies have shown that residue His39 of tPphA is critical for the enzyme's recognition of the PII protein; however, the manner in which this residue determines tPphA substrate specificity is unknown. Here, we solved the crystal structure of H39A, a tPphA variant. The structure revealed that the mutation of residue His39 to alanine changes the conformation and the flexibility of the loop in which residue His39 is located, and these changes affect the substrate specificity of tPphA. Moreover, previous studies have assumed that the FLAP subdomain and the third metal (M3) of tPphA could mutually influence each other to regulate PP2C catalytic activity and substrate specificity. However, despite the variable conformations adopted by the FLAP subdomain, the position of M3 was consistent in the tPphA structure. These results indicate that the FLAP subdomain does not influence M3 and vice versa. In addition, a small screen of tPphA inhibitors was performed. Sanguinarine and Ni 2+ were found to be the most effective inhibitors among the assayed chemicals. Finally, the dimeric form of tPphA was stabilized by cross-linkers and still exhibited catalytic activity towards p-nitrophenyl phosphate.

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A model for cardiomyocyte cell death: Insights into mechanisms of oncosis

Cited by 27 publications

References 27 publications

Oncosis: An important non-apoptotic mode of cell death

Oncosis: An important non-apoptotic mode of cell death

Glucose-deprivation increases thyroid cancer cells sensitivity to metformin

Structural and Biochemical Characterization of a Cyanobacterial PP2C Phosphatase Reveals Insights into Catalytic Mechanism and Substrate Recognition

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