Interplay Between Thiamine and p53/p21 Axes Affects Antiproliferative Action of Cisplatin in Lung Adenocarcinoma Cells by Changing Metabolism of 2-Oxoglutarate/Glutamate

Abstract

Thiamine (vitamin B1) is often deficient in oncopatients, particularly those undergoing chemotherapy. However, interaction between the thiamine deficiency and anticancer action of drugs has not been characterized. A major natural thiamine derivative, thiamine diphosphate (ThDP), is a coenzyme of central metabolism, also known to affect transcriptional activity of the master metabolic regulator and genome guardian p53. A direct transcriptional target of p53, p21, regulates cell cycle dynamics and DNA damage response. Our work focuses on dependence of the action of the DNA damaging anticancer drug cisplatin on metabolic regulation through p53/p21 axes and cellular thiamine status in human lung adenocarcinoma cells A549. These cells are used as a model of a hardly curable cancer, known to develop chemoresistance to platinum drugs, such as cisplatin. Compared to wild type (A549WT), a stable line with a 60% knockdown of p21 (A549p21–) is less sensitive to antiproliferative action of cisplatin. In contrast, in the thiamine-deficient medium, cisplatin impairs the viability of A549p21– cells more than that of A549WT cells. Analysis of the associated metabolic changes in the cells indicates that (i) p21 knockdown restricts the production of 2-oxoglutarate via glutamate oxidation, stimulating that within the tricarboxylic acid (TCA) cycle; (ii) cellular cisplatin sensitivity is associated with a 4-fold upregulation of glutamic-oxaloacetic transaminase (GOT2) by cisplatin; (iii) cellular cisplatin resistance is associated with a 2-fold upregulation of p53 by cisplatin. Correlation analysis of the p53 expression and enzymatic activities upon variations in cellular thiamine/ThDP levels indicates that p21 knockdown substitutes positive correlation of the p53 expression with the activity of 2-oxoglutarate dehydrogenase complex (OGDHC) for that with the activity of glutamate dehydrogenase (GDH). The knockdown also changes correlations of the levels of OGDHC, GDH and GOT2 with those of the malate and isocitrate dehydrogenases. Thus, a p53/p21-dependent change in partitioning of the glutamate conversion to 2-oxoglutarate through GOT2 or GDH, linked to NAD(P)-dependent metabolism of 2-oxoglutarate in affiliated pathways, adapts A549 cells to thiamine deficiency or cisplatin treatment. Cellular thiamine deficiency may interfere with antiproliferative action of cisplatin due to their common modulation of the p53/p21-dependent metabolic switch between the glutamate oxidation and transamination.

Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293

“…In pancreatic cancer cells, signaling through ERO1A is involved with metabolic reprogramming to glycolysis [ 46 ], which reduces the flux through PDHC. The recent data on the ThDP-mediated antiproliferative effect in a NSCLC cell line A549 [ 28 ] coupled to metabolic reprogramming of these cells [ 47 ], may therefore involve also ERO1A, whose expression is decreased by thiamine, as shown in our current work.…”

Physiological and Biochemical Markers of the Sex-Specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model

“…The dependence of such metabolism on vitamins may result in so-called metabolic epilepsies, often positively responding to administration of vitamins [ 44 ]. While deficiencies in vitamins B1 and B6 due to malnutrition have not been considered an issue in developed countries for a long time, these states currently occur more and more often as a result of intensified medical treatments, such as the administration of diuretics, metformin, antibiotics, chemotherapy and bariatric surgery [ 13 , 16 , 26 , 45 ]. Regarding vitamins B1 and B6, seizures are known to arise due to mutations in proteins of their transport and metabolic transformations, affecting the physiological function of the vitamins [ 46 , 47 , 48 , 49 ].…”

“…To characterize the molecular mechanisms and pathways involved, the physiological assessment is combined with the analysis of the consequences of a seizure for the brain biochemistry. In this part, the vitamin-dependent enzymes crucial for the brain metabolism of glutamate and GABA [ 1 , 2 , 22 , 23 , 24 , 25 , 26 ] are assayed, and the brain amino acid profiles [ 23 , 24 ] are quantified. As a result, we reveal sex differences in the sensitivity to PTZ administration, the biochemical markers of such differences and a dual sex-specific effect of the administration of vitamins B1 and B6 on a seizure associated with the regulation of the brain PLK activity.…”

Physiological and Biochemical Markers of the Gender-specific Sensitivity to Epileptogenic Factors, Delayed Consequences of Seizures and Their Response to Vitamins B1 and B6 in a Rat Model of Epilepsy

“…Dependence of such metabolism on vitamins may result in so called metabolic epilepsies often positively responding to administration of vitamins [26]. While deficiencies in vitamins B1 and B6 due to malnutrition have not been considered an issue in the developed countries since a long time, these states currently become more and more often as a result of intensified medical treatments, such as administration of diuretics, metformin, antibiotics, chemotherapy, bariatric surgery [13,16,24,27]. Regarding vitamins B1 and B6, seizures are known to arise due to mutations in their transport, metabolism and physiological function [28][29][30][31].…”

“…To characterize molecular mechanisms and pathways involved, the physiological assessment is combined with the analysis of the consequences of a seizure for the brain biochemistry. In this part, the vitamin-dependent enzymes crucial for the brain metabolism of glutamate and GABA [1,2,[20][21][22][23][24], are assayed, and the brain amino acid profiles [21,22] quantified. As a result, we reveal gender differences in sensitivity to PTZ administration, biochemical markers of such differences, a dual gender-specific effect of the administration of vitamins B1 and B6 on a seizure, and association of the protective effect of the vitamins on a seizure with the regulation of the brain PLK activity.…”