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Flavonoids, a subclass of polyphenols, have been shown to be effective against several types of cancer, by decreasing proliferation and inducing apoptosis. Therefore, the aim of the present study was to assess the anti-carcinogenic potential of luteolin on HeLa human cervical cancer cells, through the use of a cell viability assay, DNA fragmentation assay, mitochondrial membrane potential assay, cell cycle analysis using Annexin/PI staining and flow cytometry, gene expression analysis and a protein profiling array. Luteolin treatment exhibited cytotoxicity towards HeLa cells in a dose- and time-dependent manner, and its anti-proliferative properties were confirmed by accumulation of luteolin-treated cells in sub-G1 phases. Cytotoxicity induced by luteolin treatment resulted in apoptosis, which was mediated through depolarization of the mitochondrial membrane potential and DNA fragmentation. Furthermore, luteolin treatment increased the expression of various proapoptotic genes, including APAF1, BAX, BAD, BID, BOK, BAK1, TRADD, FADD, FAS, and Caspases 3 and 9, whereas the expression of anti-apoptotic genes, including NAIP, MCL-1 and BCL-2, was decreased. Cell cycle regulatory genes, including CCND1, 2 and 3, CCNE2, CDKN1A, CDKN2B, CDK4 and CDK2, were decreased following treatment. Expression of TRAILR2/DR5, TRAILR1/DR4, Fas/TNFRSF6/CD95 and TNFR1/TNFRSF1A, as well as pro-apoptotic proteins, including BAD, BAX and Cytochrome C were consistently increased, and the expression of antiapoptotic proteins, HIF1α, BCL-X, MCL1 and BCL2, were found to be decreased following treatment. Expression of AKT1 and 2, ELK1, PIK3C2A, PIK3C2B, MAPK14, MAP3K5, MAPK3 and MAPK1 was significantly decreased at the transcriptional level. Expression of GSK3b (p-ser9), PRAS 40 (p-Ther246), BAD (p-ser112), PTEN (p-ser380), AKT (p-ser473), ERK2 (p-Y185/Y187), RISK2 (p-ser386), P70S6k (p-Thr421/ser424), PDK1(p-ser241), ERK1 (p-T202/Y204) and MTOR (p-ser2448) was downregulated and expression of P53 (p-ser241) and P27(p-Thr198) was upregulated by luteolin in a dose-dependent manner, indicating its anti-proliferative and apoptosis enabling properties, and this may have been mediated via inhibition of the AKT and the MAPK pathways. © 2021 Spandidos Publications. All rights reserved.
apoptosis signal regulating kinase 1; apoptotic protease activating factor 1; Bcl 2 related ovarian killer; caspase 3; caspase 8; caspase 9; cyclin D1; cyclin D2; cyclin D3; cyclin dependent kinase 2; cyclin dependent kinase 4; cyclin dependent kinase inhibitor 1A; cyclin dependent kinase inhibitor 2B; cyclin E2; cytochrome c; death receptor 4; death receptor 5; dimethyl sulfoxide; ETS like 1 protein Elk 1; Fas ligand; glycogen synthase kinase 3; heat shock protein 27; hypoxia inducible factor 1 alpha; Janus kinase 2; luteolin; mammalian target of rapamycin; mitogen activated protein kinase 1; mitogen activated protein kinase 14; mitogen activated protein kinase 3; neuronal apoptosis inhibitory protein; phosphatidylinositol 3 kinase; phosphatidylinositol 3, 4, 5 trisphosphate 3 phosphatase; phosphatidylinositol 4 phosphate 3 kinase C2 domain containing alpha; phosphatidylinositol 4 phosphate 3 kinase catalytic subunit type 2 beta; polyphenol; protein BAD; protein Bax; protein bcl 2; protein Bid; protein kinase B; protein mcl 1; protein p53; serine/threonine protein kinase WNK1; stress activated protein kinase; tetramethyl rhodamine; tumor necrosis factor receptor 1; tumor necrosis factor receptor associated death domain protein; tumor necrosis factor receptor superfamily member 6; unclassified drug; Akt/mTOR signaling; apoptosis; Article; cell cycle analysis; cell cycle arrest; cell cycle assay; cell cycle G1 phase; cell cycle progression; cell cycle regulation; cell proliferation; cell viability; cell viability assay; controlled study; cytotoxicity; depolarization; DNA fragmentation; DNA fragmentation assay; DNA fragmentation assay; down regulation; drug toxicity; flow cytometry; fluorescence microscopy; G2 phase cell cycle checkpoint; gene expression; genetic susceptibility; human; human cell; IC50; MAPK signaling; mitochondrial membrane potential assay; mitochondrial membrane; MTT assay; protein expression; protein fingerprinting; regulator gene; RNA extraction; signal transduction; Western blotting
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Raina, Ritu; Pramodh, Sreepoorna; Rais, Naushad; Haque, Shafiul; Shafarin, Jasmin; Bajbouj, Khuloud; Hamad, Mawieh; and Hussain, Arif, "Luteolin inhibits proliferation, triggers apoptosis and modulates Akt/mTOR and MAP kinase pathways in HeLa cells" (2021). All Works. 2289.
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