Background: To evaluate the activity of hydrogen in endometrial cancer and elucidate its underlying molecular mechanisms.
Methods: Ishikawa, HEC1A and AN3CA cells were incubated in DMEM medium with or without hydrogen. RNA sequencing was used to explore the association of hydrogen treatment with signaling pathways and functional genes in endometrial cancer cells. The apoptotic rates of the three endometrial cancer cells were evaluated by fluorescein isothiocyanate (FITC) Annexin V and Annexin V-allophycocyanin (APC)/propidium iodide double staining.
Results: RNA sequencing analysis revealed that hydrogen induced TNF/NF-κB and apoptosis pathways in endometrial cancer cells. The gene sets between hydrogen treatment groups and non-treated groups were mapped in accordance with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms. Hydrogen treatment significantly increased the apoptotic rates of endometrial cancer cells. Conclusions: Taken together, our data indicate that hydrogen can serve as a therapeutic target for endometrial cancer via TNF/NF-κB pathway and apoptosis induction.
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-34. [Crossref] [PubMed]
Fathy SA, Mohamed MR, Ali MAM, et al. Influence of IL-6, IL-10, IFN-γ and TNF-α genetic variants on susceptibility to diabetic kidney disease in type 2 diabetes mellitus patients. Biomarkers 2019;24:43-55. [Crossref] [PubMed]
Lin CC, Edelson BT. New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. J Immunol 2017;198:4553-60. [Crossref] [PubMed]
Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860-7. [Crossref] [PubMed]
Yan Y, Jiang W, Liu L, et al. Dopamine Controls Systemic Inflammation through Inhibition of NLRP3 Inflammasome. Cell 2015;160:62-73. [Crossref] [PubMed]
Kamimura N, Nishimaki K, Ohsawa I, et al. Molecular Hydrogen Improves Obesity and Diabetes by Inducing Hepatic FGF21 and Stimulating Energy Metabolism in db/db Mice. Obesity 2011;19:1396-403. [Crossref] [PubMed]
Zhao L, Wang Y, Zhang G, et al. L-Arabinose Elicits Gut-Derived Hydrogen Production and Ameliorates Metabolic Syndrome in C57BL/6J Mice on High-Fat-Diet. Nutrients 2019; [Crossref] [PubMed]
Chen H, Zhou C, Xie K, et al. Hydrogen-rich Saline Alleviated the Hyperpathia and Microglia Activation via Autophagy Mediated Inflammasome Inactivation in Neuropathic Pain Rats. Neuroscience 2019;421:17-30. [Crossref] [PubMed]
Nakashimakamimura N, Mori T, Ohsawa I, et al. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol 2009;64:753-61. [Crossref] [PubMed]
Zhong Z, Zhai Y, Liang S, et al. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun 2013;4:1611-21. [Crossref] [PubMed]
Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 2007;13:688-94. [Crossref] [PubMed]
Uto K, Que W, Sakamoto S, et al. Hydrogen Rich Solution Attenuates Cold Ischemia-Reperfusion Injury in Rat Liver Transplantation. BMC Gastroenterol 2019;19:25-33. [PubMed]
Li L, Liu T, Liu L, et al. Effect of hydrogen-rich water on the Nrf2/ARE signaling pathway in rats with myocardial ischemia-reperfusion injury. J Bioenerg Biomembr 2019;51:393-402. [Crossref] [PubMed]
Zhang J, Zhou H, Liu J, et al. Protective effects of hydrogen inhalation during the warm ischemia phase against lung ischemia-reperfusion injury in rat donors after cardiac death. Microvasc Res 2019;125:103885. [Crossref] [PubMed]
Eryilmaz S, Turkyilmaz Z, Karabulut R, et al. The effects of hydrogen-rich saline solution on intestinal anastomosis performed after intestinal ischemia reperfusion injury. J Pediatr Surg 2019; [Epub ahead of print]. [Crossref] [PubMed]
Jorgensen I, Rayamajhi M, Miao EA. Programmed cell death as a defence against infection. Nat Rev Immunol 2017;17:151-64. [Crossref] [PubMed]
Fuentes-Prior P, Salvesen GS. The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J 2004;384:201-32. [Crossref] [PubMed]
Ooppachai C, Limtrakul DP, Yodkeeree S. Dicentrine Potentiates TNF-alpha-Induced Apoptosis and Suppresses Invasion of A549 Lung Adenocarcinoma Cells via Modulation of NF-kappaB and AP-1 Activation. Molecules 2019; [Crossref] [PubMed]
Zhang G, Li J, Purkayastha S, et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 2013;497:211-6. [Crossref] [PubMed]
Zhang Q, Lenardo MJ, Baltimore D. 30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology. Cell 2017;168:37-57. [Crossref] [PubMed]
Coto E, Reguero JR, Avanzas P, et al. Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and risk for early-onset coronary artery disease. Immunol Lett 2019;208:39-43. [Crossref] [PubMed]
Maninjay KA, Jonathan AH. Uncoupling of Pyrin-only protein 2 (POP2)-mediated dual regulation of NF-κB and the inflammasome. J Biol Chem 2011;286:40536-47. [Crossref] [PubMed]
Staples E, Morillo-Gutierrez B, Davies J, et al. DisseminatedMycobacterium malmoenseandSalmonellaInfections Associated with a Novel Variant inNFKBIA. J Clin Immunol 2017;37:415-8. [Crossref] [PubMed]
Bauernfeind F, Niepmann S, Knolle PA, et al. Aging-Associated TNF Production Primes Inflammasome Activation and NLRP3-Related Metabolic Disturbances. J Immunol 2016;197:2900-8. [Crossref] [PubMed]
Yu-Rice Y, Edassery SL, Urban N, et al. Selenium-Binding Protein 1 (SBP1) autoantibodies in ovarian disorders and ovarian cancer. Reproduction 2017;153:277-84. [Crossref] [PubMed]
Pallares J, Martínezguitarte JL, Dolcet X, et al. Abnormalities in the NF-kappaB family and related proteins in endometrial carcinoma. J Pathol 2004;204:569-77. [Crossref] [PubMed]
Vaskivuo TE, Stenbäck F, Tapanainen JS. Apoptosis and apoptosis-related factors Bcl-2, Bax, tumor necrosis factor-alpha, and NF-kappaB in human endometrial hyperplasia and carcinoma. Cancer 2002;95:1463-71. [Crossref] [PubMed]
Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461-6. [Crossref] [PubMed]
Karin M, Benneriah Y. Phosphorylation Meets Ubiquitination: The Control of NF-κB Activity. Annu Rev Immunol 2000;18:621-63. [Crossref] [PubMed]
Hattori Y, Kotani T, Tsuda H, et al. Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury. Free Radic Res 2015;49:1026-37. [Crossref] [PubMed]
Li J, Wu X, Chen Y, et al. The Effects of Molecular Hydrogen and Suberoylanilide Hydroxamic Acid on Paraquat-Induced Production of Reactive Oxygen Species and TNF-α in Macrophages. Inflammation 2016;39:1990-6. [Crossref] [PubMed]
Saitoh Y, Okayasu H, Xiao L, et al. Neutral pH hydrogen-enriched electrolyzed water achieves tumor-preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression. Oncol Res 2008;17:247-55. [Crossref] [PubMed]
Fransson AE, Marta K, Kristian P, et al. Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig. Front Cell Neurosci 2017;11:280-92. [Crossref] [PubMed]