Abstract
Although cancer cells need more glucose than normal cells to maintain energy demand, chronic hyperglycemia induces metabolic alteration that may dysregulate signaling pathways, including the O-GlcNAcylation and HIF1A (Hypoxia-inducible factor 1-alpha) pathways. Metformin was demonstrated to evoke metabolic stress and induce cancer cell death. The aim of this study was to determine the cytotoxic efficiency of metformin on SKOV-3 cells cultured in hyperglycemia and normoglycemia. To identify the potential mechanism, we assessed the expression of O-linked β-N-acetlyglucosamine transferase (OGT) and glycoside hydrolase O-GlcNAcase (OGA), as well as hypoxia-inducible factor 1-alpha (HIF1A) and glucose transporters (GLUT1, GLUT3). SKOV-3 cells were cultured in normoglycaemia (NG, 5 mM) and hyperglycemia (HG, 25 mM) with and without 10 mM metformin for 24, 48, and 72 h. The proliferation rate, apoptotic and necrotic SKOV-3 cell death were evaluated. Real-Time qPCR was employed to determine mRNA expression of OGT, OGA, GLUT1, GLUT3, and HIF1A. Metformin significantly reduced the proliferation of SKOV-3 cells under normal glucose conditions. Whereas, the efficacy of metformin to induce SKOV-3 cell death was reduced in hyperglycemia. Both hyperglycemia and metformin induced changes in the expression of genes involved in the O-GlcNAcylation status and HIF1A pathway. The obtained results suggest that dysregulation of O-GlcNAcylation, and the related HIF1A pathway, via hyperglycemia, is responsible for the decreased cytotoxic efficiency of metformin in human ovarian cancer cells.
Highlights
Ovarian cancer is one of the leading cause of death among women
Sininecde tghleuceoxspereesxspioonsuoref OcaGuTs,es OGmAet,aHboIFli1cAa,ltGerLaUtiTon1,tahnadt aGffLeUctTs 3O. -GlcNAcylation and hypoxia-inducible factor 1-alpha (HIF1A) pathway, we examined the expression of OInGteTr,eOstGinAg,lyH, IwF1eAfo, uGnLdUtTh1a,tatnhde GpLroUliTfe3r.ation of SKOV-3 cells cultured in hyperglycemia was significIanntetrlyesltoinwgelyr,inwceofmoupnadristohnattothneoprrmooligfelyracteimoniao.fTShKisOiVs-u3ncuesllusacluflotrurceadncienr hcyelplserbgelycacuemseiaitwisas wisdigenlyifaiccacneptltyedlotwhaetr hinighcogmlupcaorsiesosntimtounlaoterms porgollyifceermatiiao.nTbhyissaistisufnyuinsguaelneforgr ycaanncdercacreblolsnbneeceadusse[15it].is SiwnciedeOly-GalcccNepAtceydlatthioatnhisigshengsliuticvoesetostmimetualbaotelisc pstraotleifearnadtioisninbvyoslvateidsfiynintgumenoerrggryowantdh icnarvbitorno [n1e6e]d, s w[e15d]e.tSeirnmceinOed-GtlhceNeAxcpyrleastsioionnisosfeOnGsitTivaentdo OmGetAabmolRicNstAat.eWaendfoius nindvtohlvatedHiGn tcuamusoerdgaroswigtnhifiincavnittro
We found that HG caused a significant decrease in the expression of O-linked β-N-acetlyglucosamine transferase (OGT) and a slight increase in OGA in SKOV-3 cells
Summary
It was demonstrated that the risk of ovarian cancer is increased among diabetic patients [1]. Numerous clinical studies identified that hypoglycemic medications modulate the risk of cancer development. The drug of the first choice in type 2 diabetes mellitus treatment, was found to protect from cancer development. Experimental studies have revealed that metformin exhibited antiproliferative activity against various cancer cells. The drug was reported to inhibit the growth of ovarian cancer cells [2,3]. It is widely believed that AMPK (5 AMP-activated protein kinase) activation and inhibition of mTORC (mammalian target of rapamycin complex) are mechanisms of anticancer action of metformin. The drug was demonstrated to reduce tumorigenesis through metabolic alteration as a result of the mitochondrial respiratory complex I inhibition [3,4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
