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Article

Activation of Mitochondrial 2-Oxoglutarate Dehydrogenase by Cocarboxylase in Human Lung Adenocarcinoma Cells A549 Is p53/p21-Dependent and Impairs Cellular Redox State, Mimicking the Cisplatin Action

1
A.N. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
2
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia
3
Department of Biochemistry, Sechenov University, 119991 Moscow, Russia
4
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden
5
Common Use Center “Biobank”, Research Center for Medical Genetics, Moscow, Russia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(11), 3759; https://doi.org/10.3390/ijms21113759
Received: 8 March 2020 / Revised: 22 May 2020 / Accepted: 24 May 2020 / Published: 26 May 2020
(This article belongs to the Special Issue Mitochondria-Targeted Approaches in Health and Disease)
Genetic up-regulation of mitochondrial 2-oxoglutarate dehydrogenase is known to increase reactive oxygen species, being detrimental for cancer cells. Thiamine diphosphate (ThDP, cocarboxylase) is an essential activator of the enzyme and inhibits p53–DNA binding in cancer cells. We hypothesize that the pleiotropic regulator ThDP may be of importance for anticancer therapies. The hypothesis is tested in the present work on lung adenocarcinoma cells A549 possessing the p53–p21 pathway as fully functional or perturbed by p21 knockdown. Molecular mechanisms of ThDP action on cellular viability and their interplay with the cisplatin and p53–p21 pathways are characterized. Despite the well-known antioxidant properties of thiamine, A549 cells exhibit decreases in their reducing power and glutathione level after incubation with 5 mM ThDP, not observed in non-cancer epithelial cells Vero. Moreover, thiamine deficiency elevates glutathione in A549 cells. Viability of the thiamine deficient A549 cells is increased at a low (0.05 mM) ThDP. However, the increase is attenuated by 5 mM ThDP, p21 knockdown, specific inhibitor of the 2-oxoglutarate dehydrogenase complex (OGDHC), or cisplatin. Cellular levels of the catalytically competent ThDP·OGDHC holoenzyme are dysregulated by p21 knockdown and correlate negatively with the A549 viability. The inverse relationship between cellular glutathione and holo-OGDHC is corroborated by their comparison in the A549 and Vero cells. The similarity, non-additivity, and p21 dependence of the dual actions of ThDP and cisplatin on A549 cells manifest a common OGDHC-mediated mechanism of the viability decrease. High ThDP saturation of OGDHC compromises the redox state of A549 cells under the control of p53–p21 axes. View Full-Text
Keywords: anticancer effect of cocarboxylase; cisplatin; glutathione; 2-oxoglutarate dehydrogenase; p53; p21; thiamine anticancer effect of cocarboxylase; cisplatin; glutathione; 2-oxoglutarate dehydrogenase; p53; p21; thiamine
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MDPI and ACS Style

Bunik, V.I.; Aleshin, V.A.; Zhou, X.; Tabakov, V.Y.; Karlsson, A. Activation of Mitochondrial 2-Oxoglutarate Dehydrogenase by Cocarboxylase in Human Lung Adenocarcinoma Cells A549 Is p53/p21-Dependent and Impairs Cellular Redox State, Mimicking the Cisplatin Action. Int. J. Mol. Sci. 2020, 21, 3759. https://doi.org/10.3390/ijms21113759

AMA Style

Bunik VI, Aleshin VA, Zhou X, Tabakov VY, Karlsson A. Activation of Mitochondrial 2-Oxoglutarate Dehydrogenase by Cocarboxylase in Human Lung Adenocarcinoma Cells A549 Is p53/p21-Dependent and Impairs Cellular Redox State, Mimicking the Cisplatin Action. International Journal of Molecular Sciences. 2020; 21(11):3759. https://doi.org/10.3390/ijms21113759

Chicago/Turabian Style

Bunik, Victoria I., Vasily A. Aleshin, Xiaoshan Zhou, Vyacheslav Y. Tabakov, and Anna Karlsson. 2020. "Activation of Mitochondrial 2-Oxoglutarate Dehydrogenase by Cocarboxylase in Human Lung Adenocarcinoma Cells A549 Is p53/p21-Dependent and Impairs Cellular Redox State, Mimicking the Cisplatin Action" International Journal of Molecular Sciences 21, no. 11: 3759. https://doi.org/10.3390/ijms21113759

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