Abstract
Aim:
To determine whether the antitumor factor nm23 is related with antioxidation.
Methods:
Full-length human nm23-H1 was cloned into a mammalian-expressing vector and transiently introduced into HeLa cells.
Results:
A remarkably low level of reactive oxygen species (ROS) was detected in the cells over-expressing nm23-H1. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and trypan blue assays found that the cells transfected with a nm23-H1-expressing plasmid had higher viability and stronger resistance to oxidative stress. Immunoprecipitation tests revealed that endogenous nm23-H1 formed a protein complex with p53. Furthermore, the intracellular levels of p53 and p53-regulatedgene GPX1 were obviously increased in the cells overexpressing nm23-H1. The downregulation of p53 in the cells overexpressing nm23-H1 resulted in a higher cellular ROS level and lower cell viability.
Conclusion:
The findings suggest that nm23-H1 may act as a cellular protector against oxidative stress, possibly triggering the p53-related antioxidative pathway.
Similar content being viewed by others
Article PDF
References
Klauning JE, Kamendulis LM . The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 2004; 44: 239–67.
Bensaad K, Vousden KH . Savior and slayer: the two faces of p53. Nat Med 2005; 11: 1278–9.
Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 2006; 12: 446–51.
Storz P . Reactive oxygen species in tumor progression. Front Biosci 2005; 10: 1881–96.
Okada F, Kobayashi M, Tanaka H, Kobayashi T, Tazawa H, Luchi Y, et al. The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells. Am J Pathol 2006; 169: 294–302.
Mori K, Shibanuma M, Nose K . Invasive potential induced under long-term oxidative stress in mammary epithelial cells. Cancer Res 2004; 64: 7464–72.
Hyoudou K, Nishikawa M, Kobayashi Y, Kuramoto Y, Yamashita F, Hashida M . Inhibition of adhesion and proliferation of peritoneally disseminated tumor cells by pegylated catalase. Clin Exp Metastasis 2006; 23: 269–78.
Heirman I, Ginneberge D, Brigelius-Flohé R, Hendrickx N, Agostinis P, Brouckaert P, et al. Blocking tumor cell eicosanoid synthesis by GPX4 impedes tumor growth and malignancy. Free Radic Biol Med 2006; 40: 285–94.
Okada F, Shionoya H, Kobayashi M, Kobayashi T, Tazawa H, Onuma K, et al. Prevention of inflammation-mediated acquisition of metastatic properties of benign mouse fibrosarcoma cells by administration of an orally available superoxide dismutase. Br J Cancer 2006; 94: 854–62.
Lacombe ML, Milon L, Munier A, Mehus JG, Lambeth OD . The human Nm23/nucleoside diphosphate kinases. J Bioenerg Biomembr 2000; 32: 247–58.
Kimura N, Shimada N, Fukuda M . Regulation of cellular functions by nucleoside diphosphate kinases in mammals. J Bioenerg Biomembr 2000; 32: 309–15.
Jung H, Seong HA, Ha H . NM23-H1 tumor suppressor and its interacting partner STRAP activate p53 function. J Biol Chem 2007 30; 282: 35 293–307.
Arnaud-Dabernat S, Masse K, Smani M, Peuchant E, Landry M, Bourbon PM, et al. Nm23-M2/NDP kinase B induces endogenous c-myc and nm23-M1/NDP kinase A over-expression in BAF3 cells. Both NDP kinases protect the cells from oxidative stress-induced death. Exp Cell Res 2004; 301: 293–304.
Hussain SP, Amstad P, He P, Robles A, Lupold S, Kaneko I, et al. p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Res 2004; 64: 2350–6.
Yoon KA, Nakamura Y, Arakawa H . Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J Hum Genet 2004; 49: 134–40.
Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM . The antioxidant function of the p53 tumor suppressor. Nat Med 2005; 11: 1306–13.
de la Rosa A, Williams RL, Steeg PS . Nm23/nucleoside diphosphate kinase: toward a structural and biochemical understanding of its biological functions. Bioessays 1995; 17: 53–62.
Benhar M, Engelberg D, Levitzki A . ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep 2002; 3: 420–5.
Postel EH . Multiple biochemical activities of NM23/NDP kinase in gene regulation. J Bioenerg Biomembr 2003; 35: 31–40.
Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J . Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 2003; 112: 659–72.
Seong HA, Jung H, Ha H . NM23-H1 tumor suppressor physically interacts with serine-threonine kinase receptor-associated protein, a transforming growth factor-beta (TGF-beta) receptor-interacting protein, and negatively regulates TGF-beta signaling. J Biol Chem 2007; 282: 12 075–96.
Rayner K, Chen YX, Hibbert B, White D, Miller H, Postel EH, et al. Discovery of NM23-H2 as an estrogen receptor beta-associated protein: role in estrogen-induced gene transcription and cell migration. J Steroid Biochem Mol Biol 2008; 108: 72–81.
Chu FF, Doroshow JH, Esworthy RS . Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI. J Biol Chem 1993; 268: 2571–6.
Ding B, Chi SG, Kim SH, Kang S, Cho JH, Kim DS, et al. Role of p53 in antioxidant defense of HPV-positive cervical carcinoma cells following H2O2 exposure. J Cell Sci 2007; 120: 2284–94.
Macip S, Igarashi M, Berggren P, Yu J, Lee SW, Aaronson SA . Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol Cell Biol 2003; 23: 8576–85.
Sengupta S, Harris CC . p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol 2005; 6: 44–55.
Nicco C, Laurent A, Chereau C, Weill B, Batteux F . Differential modulation of normal and tumor cell proliferation by reactive oxygen species. Biomed Pharmacother 2005; 59: 169–74.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by the National Science and Technology Task Force Project (No 2006BAD06A13-2), the National Basic Research Program of China (973 Program) (No 2007CB310505), and National Natural Science Foundation of China (No 30571672, 30500018, and 30771914).
Rights and permissions
About this article
Cite this article
An, R., Chu, Yl., Tian, C. et al. Over-expression of nm23-H1 in HeLa cells provides cells with higher resistance to oxidative stress possibly due to raising intracellular p53 and GPX1. Acta Pharmacol Sin 29, 1451–1458 (2008). https://doi.org/10.1111/j.1745-7254.2008.00902.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2008.00902.x
Keywords
This article is cited by
-
Expression profiles of p53/p73, NME and GLI families in metastatic melanoma tissue and cell lines
Scientific Reports (2019)
-
Distinguishing between cancer cell differentiation and resistance induced by all-trans retinoic acid using transcriptional profiles and functional pathway analysis
Scientific Reports (2015)
-
Erythropoietin Increases Neuronal NDPKA Expression, and NDPKA Up-Regulation as well as Exogenous Application Protects Cortical Neurons from In Vitro Ischemia-Related Insults
Cellular and Molecular Neurobiology (2014)
-
Protein histidine [de]phosphorylation in insulin secretion: abnormalities in models of impaired insulin secretion
Naunyn-Schmiedeberg's Archives of Pharmacology (2011)