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Nitric oxide induces HepG2 cell death via extracellular signal-regulated protein kinase activation by regulating acid sphingomyelinase

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Abstract

Nitric oxide (NO) plays a vital role in the occurrence and development of tumours. Acid sphingomyelinase (ASM) participates in cell apoptosis, cell proliferation, metabolism and other biological processes. However, whether ASM has an effect on NO-treated HepG2 cells remains unknown, and the role of the extracellular signal-regulated protein kinase (ERK) pathway is also unclear. In the present study, the effects of NO on cell viability and apoptosis were assayed, followed by investigating the mRNA and protein levels of ASM and ERK phosphorylation in NO-treated HepG2 cells. The results showed that diethylenetriamine/NO (DETA–NO), an NO donor, promoted HepG2 cell death and apoptosis in a concentration-dependent manner and that the mRNA and protein expression levels of ASM were significantly decreased in DETA–NO-treated HepG2 cells. Moreover, ERK phosphorylation was significantly increased in DETA–NO-treated HepG2 cells. The inhibition of ERK phosphorylation increased DETA–NO-induced cell apoptosis. In summary, DETA–NO can promote HepG2 cell death in a concentration-dependent manner by activating ERK and NO might activate ERK by regulating ASM and then inducing HepG2 cell death.

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References

  1. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87(1):315–424

    Article  CAS  Google Scholar 

  2. Amin AR (2012) The metabolomics of nitric oxide and reactive nitrogen species in immune editing tumor milieu: influence of nitric oxide-modulating therapies. J Drug Metab Toxicol S 8:2

    Google Scholar 

  3. Blaise GA, Gauvin D, Gangal M et al (2005) Nitric oxide, cell signaling and cell death. Toxicology 208(2):177–192

    Article  CAS  Google Scholar 

  4. Schroeter H, Boyd C, Spencer JP et al (2002) MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Aging 23(5):861–880

    Article  CAS  Google Scholar 

  5. Oláh G, Módis K, Törö G et al (2018) Role of endogenous and exogenous nitric oxide, carbon monoxide and hydrogen sulfide in HCT116 colon cancer cell proliferation. Biochem Pharmacol 149:186–204

    Article  Google Scholar 

  6. Hwang JH, Park SJ, Ko WG et al (2017) Cordycepin induces human lung cancer cell apoptosis by inhibiting nitric oxide mediated ERK/Slug signaling pathway. Am J Cancer Res 7(3):417–432

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Gorelik A, Illes K, Heinz LX et al (2016) Crystal structure of mammalian acid sphingomyelinase. Nat Commun 7:12196

    Article  CAS  Google Scholar 

  8. Leurs CE, Lopes Pinheiro MA, Wierts L et al (2019) Acid sphingomyelinase: No potential as a biomarker for multiple sclerosis. Mul Scler Relat Disord 28:44–49

    Article  CAS  Google Scholar 

  9. Saftig P, Sandhoff K (2013) Cancer: killing from the inside. Nature 502(7471):312–313

    Article  CAS  Google Scholar 

  10. Henry B, Ziobro R, Becker KA et al (2013) Acid sphingomyelinase. Sphingolipids: basic science and drug development. Handb Exp Pharmacol 215:77–88

    Article  CAS  Google Scholar 

  11. Zhang Y, Duan RD (2009) Boswellic acid inhibits expression of acid sphingomyelinase in intestinal cells. Lipids Health Dis 8:51

    Article  Google Scholar 

  12. Wu J, Cheng Y, Jonsson BA et al (2005) Acid sphingomyelinase is induced by butyrate but does not initiate the anticancer effect of butyrate in HT29 and HepG2 cells. J Lipid Res 46(9):1944–1952

    Article  CAS  Google Scholar 

  13. Kachler K, Bailer M, Heim L et al (2017) Enhanced acid sphingomyelinase activity drives immune evasion and tumor growth in non-small cell lung carcinoma. Cancer Res 77(21):5963–5976

    Article  CAS  Google Scholar 

  14. Kady N, Yan Y, Salazar T et al (2017) Increase in acid sphingomyelinase level in human retinal endothelial cells and CD34+ circulating angiogenic cells isolated from diabetic individuals is associated with dysfunctional retinal vasculature and vascular repair process in diabetes. J Clin Lipidol 11(3):694–703

    Article  Google Scholar 

  15. Perrotta C, Clementi E (2010) Biological roles of acid and neutral sphingomyelinases and their regulation by nitric oxide. Physiology 25(2):64–71

    Article  CAS  Google Scholar 

  16. Zhou Y, Salker MS, Walker B et al (2016) Acid sphingomyelinase (ASM) is a negative regulator of regulatory T cell (Treg) development. Cell Physiol Biochem 39(3):985–995

    Article  CAS  Google Scholar 

  17. Carpinteiro A, Beckmann N, Seitz A et al (2016) Role of acid sphingomyelinase-induced signaling in melanoma cells for hematogenous tumor metastasis. Cell Physiol Biochem 38(1):1–14

    Article  CAS  Google Scholar 

  18. Niaudet C, Bonnaud S, Guillonneau M et al (2017) Plasma membrane reorganization links acid sphingomyelinase/ceramide to p38 MAPK pathways in endothelial cells apoptosis. Cell Signal 33:10–21

    Article  CAS  Google Scholar 

  19. Taha TA, Osta W, Kozhaya L et al (2004) Down-regulation of sphingosine kinase-1 by DNA damage: dependence on proteases and p53. J Biol Chem 279(19):20546–20554

    Article  CAS  Google Scholar 

  20. Zhang H, Kong WJ, Shan YQ et al (2010) Protein kinase D activation stimulates the transcription of the insulin receptor gene. Mol Cell Endocrinol 330(1–2):25–32

    Article  CAS  Google Scholar 

  21. Zhou L, Zhang H, Wu J (2016) Effects of nitric oxide on the biological behavior of HepG2 human hepatocellular carcinoma cells. Exp Ther Med 11(5):1875–1880

    Article  CAS  Google Scholar 

  22. Zhang X, Jin L, Tian Z et al (2019) Nitric oxide inhibits autophagy and promotes apoptosis in hepatocellular carcinoma. Cancer Sci 110(3):1054–1063

    Article  CAS  Google Scholar 

  23. Rodrigues FP, Carneiro ZA, Mascharak P et al (2016) Incorporation of a ruthenium nitrosyl complex into liposomes, the nitric oxide released from these liposomes and HepG2 cell death mechanism. Coord Chem Rev 306:701–707

    Article  CAS  Google Scholar 

  24. Liu L, Wang D, Wang J et al (2016) The nitric oxide prodrug JS-K induces Ca2+-mediated apoptosis in human hepatocellular carcinoma HepG2 cells. J Biochem Mol Toxicol 30(4):192–199

    Article  CAS  Google Scholar 

  25. Zile H, Ling L, Jingjing C et al (2018) JS-K as a nitric oxide donor induces apoptosis via the ROS/Ca2+/caspase-mediated mitochondrial pathway in HepG2 cells. Biomed Pharmacother 107:1385–1392

    Article  Google Scholar 

  26. Chen Y, Xu SC, Duan RD (2015) Mevalonate inhibits acid sphingomyelinase activity, increases sphingomyelin levels and inhibits cell proliferation of HepG2 and Caco-2 cells. Lipids Health Dis 14:130

    Article  Google Scholar 

  27. Ceccarini MR, Codini M, Cataldi S et al (2016) Acid sphingomyelinase as target of Lycium Chinense: promising new action for cell health. Lipids Health Dis 15(1):183

    Article  Google Scholar 

  28. Lee JK, Jin HK, Park MH et al (2014) Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease. J Exp Med 211(8):1551–1570

    Article  CAS  Google Scholar 

  29. Cagnol S, Chambard JC (2010) ERK and cell death: mechanisms of ERK-induced cell death–apoptosis, autophagy and senescence. FEBS J 277(1):2–21

    Article  CAS  Google Scholar 

Download references

Funding

This study was funded by the National Natural Science Foundation of China (No. 21561006 and No. 21867007), Science and Technology Foundation of Guizhou Province (No.[2019]1258, No. LH-[2016]7372 and No. J-[2014]2028).

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Authors and Affiliations

  1. Immune Cells and Antibody Engineering Research Center of Guizhou Province, Guizhou Medical University, Guiyang, 550000, Guizhou, People’s Republic of China

    Liangliang Zhang, Jie Dai & Yi Jia

  2. Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, 550000, Guizhou, People’s Republic of China

    Liangliang Zhang, Jie Dai, Zhu Zeng & Yi Jia

  3. Engineering Research Center of Medical Biotechnology, Guizhou Medical University, Guiyang, 550000, Guizhou, People’s Republic of China

    Liangliang Zhang, Jie Dai & Yi Jia

  4. School of Basic Medical Science, Guizhou Medical University, Guiyang, 550000, Guizhou, People’s Republic of China

    Zhu Zeng

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  1. Liangliang Zhang
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  2. Jie Dai
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  3. Zhu Zeng
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  4. Yi Jia
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Correspondence to Zhu Zeng or Yi Jia.

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Zhang, L., Dai, J., Zeng, Z. et al. Nitric oxide induces HepG2 cell death via extracellular signal-regulated protein kinase activation by regulating acid sphingomyelinase. Mol Biol Rep 47, 8353–8359 (2020). https://doi.org/10.1007/s11033-020-05881-x

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  • DOI: https://doi.org/10.1007/s11033-020-05881-x

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