Alpha Ketoglutarate Levels, Regulated by P53 and OGDH, Determine Autophagy and Cell Fate/apoptosis in Response to Nutlin-3a

Overview

Journal Cancer Biol Ther

Specialties Oncology
Pharmacology

Date 2018 Oct 6

PMID 30289354

Citations 10

Authors

Lei Duan

Ricardo E Perez

Carl G Maki

Affiliations

Soon will be listed here.

Abstract

Activated p53 can promote apoptosis or cell cycle arrest. Differences in energy metabolism can influence cell fate in response to activated p53. Nutlin-3a is a preclinical drug and small molecule activator of p53. Alpha-ketoglutarate (αKG) levels were reduced in cells sensitive to Nutlin-3a-induced apoptosis and increased in cells resistant to this apoptosis. Add-back of a cell-permeable αKG analog (DMKG) rescued cells from apoptosis in response to Nutlin-3a. OGDH is a component of the αKGDH complex that converts αKG to succinate. OGDH knockdown increased endogenous αKG levels and also rescued cells from Nutlin-3a-induced apoptosis. We previously showed reduced autophagy and ATG gene expression contributes to Nutlin-3a-induced apoptosis. DMKG and OGDH knockdown restored autophagy and ATG gene expression in Nutlin-3a-treated cells. These studies indicate αKG levels, regulated by p53 and OGDH, determine autophagy and apoptosis in response to Nutlin-3a.

Citing Articles

β-Glucans in particulate and solubilized forms elicit varied immunomodulatory and apoptosis effects in teleost macrophages in a dosedependent manner.

Wu Z, Yang Y, Li J, Bossier P, Wei X, Guo Z Front Immunol. 2023; 14:1243358.

PMID: 37675105 PMC: 10477985. DOI: 10.3389/fimmu.2023.1243358.

The α-Ketoglutarate Dehydrogenase Complex as a Hub of Plasticity in Neurodegeneration and Regeneration.

Hansen G, Gibson G Int J Mol Sci. 2022; 23(20).

PMID: 36293260 PMC: 9603878. DOI: 10.3390/ijms232012403.

Targeting 2-oxoglutarate dehydrogenase for cancer treatment.

Chang L, Chiang S, Chen S, Hung M Am J Cancer Res. 2022; 12(4):1436-1455.

PMID: 35530286 PMC: 9077069.

Oncogenesis induced by combined Phf6 and Idh2 mutations through increased oncometabolites and impaired DNA repair.

Chen T, Yao C, Chen Y, Yuan C, Lin C, Hsu Y Oncogene. 2022; 41(11):1576-1588.

PMID: 35091680 DOI: 10.1038/s41388-022-02193-1.

Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?.

Haronikova L, Bonczek O, Zatloukalova P, Kokas-Zavadil F, Kucerikova M, Coates P Cell Mol Biol Lett. 2021; 26(1):53.

PMID: 34911439 PMC: 8903693. DOI: 10.1186/s11658-021-00293-6.

References

Teperino R, Schoonjans K, Auwerx J . Histone methyl transferases and demethylases; can they link metabolism and transcription?. Cell Metab. 2010; 12(4):321-327. PMC: 3642811. DOI: 10.1016/j.cmet.2010.09.004. View

Zawacka-Pankau J, Grinkevich V, Hunten S, Nikulenkov F, Gluch A, Li H . Inhibition of glycolytic enzymes mediated by pharmacologically activated p53: targeting Warburg effect to fight cancer. J Biol Chem. 2011; 286(48):41600-41615. PMC: 3308870. DOI: 10.1074/jbc.M111.240812. View

Duan L, Danzer B, Levenson V, Maki C . Critical roles for nitric oxide and ERK in the completion of prosurvival autophagy in 4OHTAM-treated estrogen receptor-positive breast cancer cells. Cancer Lett. 2014; 353(2):290-300. PMC: 4827626. DOI: 10.1016/j.canlet.2014.07.031. View

Carvajal L, Manfredi J . Another fork in the road--life or death decisions by the tumour suppressor p53. EMBO Rep. 2013; 14(5):414-21. PMC: 3642373. DOI: 10.1038/embor.2013.25. View

Szulc J, Wiznerowicz M, Sauvain M, Trono D, Aebischer P . A versatile tool for conditional gene expression and knockdown. Nat Methods. 2006; 3(2):109-16. DOI: 10.1038/nmeth846. View

Saxton R, Sabatini D . mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017; 169(2):361-371. DOI: 10.1016/j.cell.2017.03.035. View

Duan L, Perez R, Davaadelger B, Dedkova E, Blatter L, Maki C . p53-regulated autophagy is controlled by glycolysis and determines cell fate. Oncotarget. 2015; 6(27):23135-56. PMC: 4695109. DOI: 10.18632/oncotarget.5218. View

Aziz M, Shen H, Maki C . Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3. Oncogene. 2011; 30(46):4678-86. PMC: 3347888. DOI: 10.1038/onc.2011.185. View

White E, Mehnert J, Chan C . Autophagy, Metabolism, and Cancer. Clin Cancer Res. 2015; 21(22):5037-46. PMC: 4646728. DOI: 10.1158/1078-0432.CCR-15-0490. View

10.

Chin R, Fu X, Pai M, Vergnes L, Hwang H, Deng G . The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014; 510(7505):397-401. PMC: 4263271. DOI: 10.1038/nature13264. View

11.

Matoba S, Kang J, Patino W, Wragg A, Boehm M, Gavrilova O . p53 regulates mitochondrial respiration. Science. 2006; 312(5780):1650-3. DOI: 10.1126/science.1126863. View

12.

Tsukada Y, Fang J, Erdjument-Bromage H, Warren M, Borchers C, Tempst P . Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2005; 439(7078):811-6. DOI: 10.1038/nature04433. View

13.

Pavlova N, Thompson C . The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016; 23(1):27-47. PMC: 4715268. DOI: 10.1016/j.cmet.2015.12.006. View

14.

Suzuki S, Tanaka T, Poyurovsky M, Nagano H, Mayama T, Ohkubo S . Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A. 2010; 107(16):7461-6. PMC: 2867754. DOI: 10.1073/pnas.1002459107. View

15.

Munafo D, Colombo M . A novel assay to study autophagy: regulation of autophagosome vacuole size by amino acid deprivation. J Cell Sci. 2001; 114(Pt 20):3619-29. DOI: 10.1242/jcs.114.20.3619. View

16.

Davaadelger B, Perez R, Zhou Y, Duan L, Gitelis S, Maki C . The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis. Cancer Biol Ther. 2017; 18(11):895-903. PMC: 5710671. DOI: 10.1080/15384047.2017.1345397. View

17.

Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y . Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell. 2012; 149(6):1269-83. PMC: 3688046. DOI: 10.1016/j.cell.2012.04.026. View

18.

Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z . Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci U S A. 2010; 107(16):7455-60. PMC: 2867677. DOI: 10.1073/pnas.1001006107. View

19.

Zhao J, Peng L, Cui R, Guo X, Yan M . Dimethyl α-ketoglutarate reduces CCl-induced liver fibrosis through inhibition of autophagy in hepatic stellate cells. Biochem Biophys Res Commun. 2016; 481(1-2):90-96. DOI: 10.1016/j.bbrc.2016.11.010. View

20.

Zhou Y, Perez R, Duan L, Maki C . DZNep represses Bcl-2 expression and modulates apoptosis sensitivity in response to Nutlin-3a. Cancer Biol Ther. 2018; 19(6):465-474. PMC: 5927691. DOI: 10.1080/15384047.2018.1433500. View