Combined Transcriptomics and Chemical-Genetics Reveal Molecular Mode of Action of Valproic acid, an Anticancer Molecule using Budding Yeast Model

Golla, Upendarrao; Joseph, Deepthi; Tomar, Raghuvir Singh

doi:10.1038/srep35322

Cited by 21 publications

(10 citation statements)

References 55 publications

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“…This may demonstrate an increased need for NADPH, which is generated only during the oxidative phase. VPA increases reactive oxygen species levels and induces the oxidative stress response in yeast 51,52 . Therefore, cells may require increased NADPH, which is utilized to reduce glutathione that is essential to neutralize reactive oxygen species.…”

Section: Resultsmentioning

confidence: 99%

Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae

Salsaa

Pereira

Liu

et al. 2020

Sci Rep

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the widely used mood stabilizer valproate (VpA) causes perturbation of energy metabolism, which is implicated in both the therapeutic mechanism of action of the drug as well as drug toxicity. to gain insight into these mechanisms, we determined the effects of VPA on energy metabolism in yeast. VpA treatment increased levels of glycolytic intermediates, increased expression of glycolysis genes, and increased ethanol production. increased glycolysis was likely a response to perturbation of mitochondrial function, as reflected in decreased membrane potential and oxygen consumption. interestingly, yeast, mouse liver, and isolated bovine cytochrome c oxidase were directly inhibited by the drug, while activities of other oxidative phosphorylation complexes (III and V) were not affected. These findings have implications for mechanisms of therapeutic action and toxicity. Bipolar disorder (BD) is a severe psychiatric illness characterized by shifts in mood, ranging from mania to depression. It affects at least 1% of the population and leads to suicide in 15% of cases 1. BD patients exhibit a higher prevalence of obesity, cardiovascular disease, and diabetes than the general population 2,3. Many studies have shown that the pathophysiology of BD involves altered energy metabolism 4-8. While most of the metabolic markers measured indicate mitochondrial dysfunction in BD 9-12 , some studies have suggested the presence of increased mitochondrial activity in the manic phase of BD 13 , including increased energy generation 14 , basal metabolic rate 15 , uric acid 16 , and calcium ions 17. Valproate (VPA) is one of several mood stabilizers approved by the FDA for the treatment of BD 18,19 , epilepsy 20,21 , and migraine 22. The mechanism of action of VPA is not understood 23. VPA is effective in only 40-60% of cases and can cause serious side effects, including hepatotoxicity and teratogenicity 24. Hepatotoxicity can be life-threatening 25,26 and may occur even at therapeutic doses 27. Although rare, lethal hepatotoxicity associated with VPA has been described in both children 28 and adults 29. The prominent feature of this type of hepatotoxicity is microvesicular steatosis 30 , consistent with mitochondrial dysfunction 31. In agreement with this, patients with congenital defects in mitochondrial metabolism are at a higher risk for susceptibility to VPA toxicity 32-34. VPA exerts numerous documented effects on mitochondrial metabolism. It is metabolized by and inhibits ß-oxidation through several mechanisms 35. VPA and its metabolites sequester coenzyme A (CoA), depleting mitochondrial CoA 36. Furthermore, studies suggest that both unesterified VPA as well as VPA acyl-CoA esters inhibit fatty acid oxidation enzymes 37,38. In addition to affecting ß-oxidation, VPA inhibits α-ketoglutarate dehydrogenase, a key enzyme of the tricarboxylic acid (TCA) cycle 39,40. Inhibition of this enzyme is a proposed mechanism underlying decreased TCA cycle flux in the presence of VPA 41. VPA also decreases levels of carnitine 42,43 , which transpo...

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Section: Resultsmentioning

confidence: 99%

Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae

Salsaa

Pereira

Liu

et al. 2020

Sci Rep

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“…Previous studies have found that cells lacking mitochondrial respiration generally have low viability due to hypersensitivity to various stresses such as hydrogen peroxide, ethanol, and heat [ 38 , 56 , 57 ]. Furthermore, the tolerance for intracellular ROS varies depending on the difference of genetic background among the laboratory strains [ 58 ]. Taking all of the above into consideration, it is plausible that RLS of respiratory-deficient mutants is influenced by the resistance to accumulated ROS, which is different among the laboratory strains.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction reduces yeast replicative lifespan by elevating RAS-dependent ROS production by the ER-localized NADPH oxidase Yno1

Hong

Huh

2018

PLoS ONE

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Mitochondrial dysfunction leads to the accumulation of reactive oxygen species (ROS) which is associated with cellular dysfunction, disease etiology, and senescence. Here, we used the eukaryotic model Saccharomyces cerevisiae, commonly studied for cellular aging, to demonstrate how defective mitochondrial function affects yeast replicative lifespan (RLS). We show that RLS of respiratory-deficient cells decreases significantly, indicating that the maintenance of RLS requires active respiration. The shortening of RLS due to mitochondrial dysfunction was not related to the accumulation of extrachromosomal ribosomal DNA circles, a well-known cause of aging in yeast. Instead, intracellular ROS and oxidatively damaged proteins increased in respiratory-deficient mutants. We show that, while the protein kinase A activity is not elevated, ROS generation in respiratory-deficient cells depends on RAS signaling pathway. The ER-localized NADPH oxidase Yno1 also played a role in producing ROS. Our data suggest that a severe defect in mitochondrial respiration accelerates cellular aging by disturbing protein homeostasis in yeast.

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“…The β -galactosidase assay was performed to monitor the expression levels of UPRE-lacZ reporter gene as described previously [ 125 ]. Briefly, the exponentially growing wild-type (BY4741) yeast cells (OD 600 : 0.8-1) carrying 2μ UPRE-lacZ reporter plasmid ( pPW344 ; gifted by Laran T. Jensen) [ 126 ] were treated with either DMSO (solvent control) or indicated doses of KP1019 (50, 100 μg/ml; 3h) and tunicamycin (1μg/ml; 1h) in SC (Ura dropped) media.…”

Section: Methodsmentioning

confidence: 99%

A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A)

et al. 2017

Self Cite

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KP1019 ([trans-RuCl4(1H-indazole)2]; FFC14A) is one of the promising ruthenium-based anticancer drugs undergoing clinical trials. Despite the pre-clinical and clinical success of KP1019, the mode of action and various factors capable of modulating its effects are largely unknown. Here, we used transcriptomics and genetic screening approaches in budding yeast model and deciphered various genetic targets and plethora of cellular pathways including cellular signaling, metal homeostasis, vacuolar transport, and lipid homeostasis that are primarily targeted by KP1019. We also demonstrated that KP1019 modulates the effects of TOR (target of rapamycin) signaling pathway and induces accumulation of neutral lipids (lipid droplets) in both yeast and HeLa cells. Interestingly, KP1019-mediated effects were found augmented with metal ions (Al3+/Ca2+/Cd2+/Cu2+/Mn2+/Na+/Zn2+), and neutralized by Fe2+, antioxidants, osmotic stabilizer, and ethanolamine. Additionally, our comprehensive screening of yeast histone H3/H4 mutant library revealed several histone residues that could significantly modulate the KP1019-induced toxicity. Altogether, our findings in both the yeast and HeLa cells provide molecular insights into mechanisms of action of KP1019 and various factors (chemical/genetic/epigenetic) that can alter the therapeutic efficiency of this clinically important anticancer drug.

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Combined Transcriptomics and Chemical-Genetics Reveal Molecular Mode of Action of Valproic acid, an Anticancer Molecule using Budding Yeast Model

Cited by 21 publications

References 55 publications

Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae

Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae

Mitochondrial dysfunction reduces yeast replicative lifespan by elevating RAS-dependent ROS production by the ER-localized NADPH oxidase Yno1

A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A)

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