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Curcumin downregulates the PI3K–AKT–mTOR pathway and inhibits growth and progression in head and neck cancer cells
dc.contributor.authorBorges, Gabriel Alvares
dc.contributor.authorElias, Silvia Taveira
dc.contributor.authorAmorim, Bruna
dc.contributor.authorLima, Caroline Lourenço
dc.contributor.authorColetta, Ricardo Della
dc.contributor.authorCastilho, Rogerio Moraes
dc.contributor.authorSquarize, Cristiane Helena
dc.contributor.authorGuerra, Eliete Neves Silva
dc.date.accessioned2021-01-05T18:48:06Z
dc.date.availableWITHHELD_12_MONTHS
dc.date.available2021-01-05T18:48:06Z
dc.date.issued2020-12
dc.identifier.citationBorges, Gabriel Alvares; Elias, Silvia Taveira; Amorim, Bruna; Lima, Caroline Lourenço ; Coletta, Ricardo Della; Castilho, Rogerio Moraes; Squarize, Cristiane Helena; Guerra, Eliete Neves Silva (2020). "Curcumin downregulates the PI3K–AKT–mTOR pathway and inhibits growth and progression in head and neck cancer cells." Phytotherapy Research 34(12): 3311-3324.
dc.identifier.issn0951-418X
dc.identifier.issn1099-1573
dc.identifier.urihttps://hdl.handle.net/2027.42/163924
dc.description.abstractCurcumin, a polyphenol isolated from the rhizome of Curcuma longa, has been studied because of its antioxidant, antimicrobial, and antiinflammatory properties. This study aimed to evaluate the effects of curcumin on head and neck cancer (HNC) cell lines and how it modulates the PI3K–AKT–mTOR signaling pathway. Dose‐response curves for curcumin were established for hypopharynx carcinoma (FaDu), tongue carcinoma (SCC‐9), and keratinocytes (HaCaT) cell lines and IC50 values were calculated. Cell cycle and cell death were investigated through flow cytometry. Cytoskeleton organization was assessed through phalloidin+FITC staining. qPCR array and western blot were performed to analyze gene and protein expression. Curcumin reduced cell viability in a dose‐dependent and selective manner, induced cell death on SCC‐9 cells (necrosis/late apoptosis: 44% curcumin vs. 16.4% vehicle), and arrested cell cycle at phase G2/M on SCC‐9 and FaDu (G2: SCC‐9—19.1% curcumin vs. 13.4% vehicle; FaDu—37.8% curcumin vs. 12.9% vehicle). Disorganized cytoskeleton and altered cell morphology were observed. Furthermore, curcumin downregulated the PI3K–AKT–mTOR signaling pathway by modifying the expression of key genes and proteins. These findings highlight the promising therapeutic potential of curcumin to inhibit HNC growth and progression and to modulate the PI3K–AKT–mTOR pathway.
dc.publisherJohn Wiley & Sons, Ltd.
dc.subject.otherhead and neck cancer
dc.subject.othercytoskeleton
dc.subject.othercurcumin
dc.subject.othercell death
dc.subject.othercell cycle
dc.subject.otherPI3K–AKT–mTOR pathway
dc.titleCurcumin downregulates the PI3K–AKT–mTOR pathway and inhibits growth and progression in head and neck cancer cells
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelBiological Chemistry
dc.subject.hlbsecondlevelChemistry
dc.subject.hlbtoplevelScience
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/163924/1/ptr6780.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/163924/2/ptr6780_am.pdf
dc.identifier.doi10.1002/ptr.6780
dc.identifier.sourcePhytotherapy Research
dc.identifier.citedreferenceNoureddin, S. A., El‐Shishtawy, R. M., & Al‐Footy, K. O. ( 2019 ). Curcumin analogues and their hybrid molecules as multifunctional drugs. European Journal of Medicinal Chemistry, 182, 111631. https://doi.org/10.1016/j.ejmech.2019.111631
dc.identifier.citedreferenceFerguson, J. J. A., Stojanovski, E., MacDonald‐Wicks, L., & Garg, M. L. ( 2018 ). Curcumin potentiates cholesterol‐lowering effects of phytosterols in hypercholesterolaemic individuals. A randomised controlled trial. Metabolism, 82, 22 – 35. https://doi.org/10.1016/j.metabol.2017.12.009
dc.identifier.citedreferenceGattoc, L., Frew, P. M., Thomas, S. N., Easley, K. A., Ward, L., Chow, H. S., … Flowers, L. ( 2017 ). Phase I dose‐escalation trial of intravaginal curcumin in women for cervical dysplasia. Open Access Journal of Clinical Trials, 9, 1 – 10. https://doi.org/10.2147/OAJCT.S105010
dc.identifier.citedreferenceIsakov, N. ( 2018 ). Protein kinase C (PKC) isoforms in cancer, tumor promotion and tumor suppression. Seminars in Cancer Biology, 48, 36 – 52. https://doi.org/10.1016/j.semcancer.2017.04.012
dc.identifier.citedreferenceIzzo, A. A. ( 2020 ). An updated PTR virtual issue on the pharmacology of the nutraceutical curcumin. Phytotherapy Research, 34 ( 4 ), 671 – 673. https://doi.org/10.1002/ptr.6635
dc.identifier.citedreferenceJazayeri‐Tehrani, S. A., Rezayat, S. M., Mansouri, S., Qorbani, M., Alavian, S. M., Daneshi‐Maskooni, M., & Hosseinzadeh‐Attar, M. J. ( 2019 ). Nano‐curcumin improves glucose indices, lipids, inflammation, and Nesfatin in overweight and obese patients with non‐alcoholic fatty liver disease (NAFLD): A double‐blind randomized placebo‐controlled clinical trial. Nutrition and Metabolism, 16, 8. https://doi.org/10.1186/s12986-019-0331-1
dc.identifier.citedreferenceJones, M. C., Zha, J., & Humphries, M. J. ( 2019 ). Connections between the cell cycle, cell adhesion and the cytoskeleton. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 374 ( 1779 ), 20180227. https://doi.org/10.1098/rstb.2018.0227
dc.identifier.citedreferenceKahkhaie, K. R., Mirhosseini, A., Aliabadi, A., Mohammadi, A., Mousavi, M. J., Haftcheshmeh, S. M., … Sahebkar, A. ( 2019 ). Curcumin: A modulator of inflammatory signaling pathways in the immune system. Inflammopharmacology, 27 ( 5 ), 885 – 900. https://doi.org/10.1007/s10787-019-00607-3
dc.identifier.citedreferenceKanai, M., Otsuka, Y., Otsuka, K., Sato, M., Nishimura, T., Mori, Y., … Shibata, H. ( 2013 ). A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients. Cancer Chemotherapy and Pharmacology, 71 ( 6 ), 1521 – 1530. https://doi.org/10.1007/s00280-013-2151-8
dc.identifier.citedreferenceKotha, R. R., & Luthria, D. L. ( 2019 ). Curcumin: Biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules, 24 ( 16 ), 2930. https://doi.org/10.3390/molecules24162930
dc.identifier.citedreferenceKunnumakkara, A. B., Bordoloi, D., Padmavathi, G., Monisha, J., Roy, N. K., Prasad, S., & Aggarwal, B. B. ( 2017 ). Curcumin, the golden nutraceutical: Multitargeting for multiple chronic diseases. British Journal of Pharmacology, 174 ( 11 ), 1325 – 1348. https://doi.org/10.1111/bph.13621
dc.identifier.citedreferenceLaplante, M., & Sabatini, D. M. ( 2012 ). mTOR signaling in growth control and disease. Cell, 149 ( 2 ), 274 – 293. https://doi.org/10.1016/j.cell.2012.03.017
dc.identifier.citedreferenceLin, S. R., Chang, C. H., Hsu, C. F., Tsai, M. J., Cheng, H., Leong, M. K., … Weng, C. F. ( 2020 ). Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence. British Journal of Pharmacology, 177 ( 6 ), 1409 – 1423. https://doi.org/10.1111/bph.14816
dc.identifier.citedreferenceLiu, F., Gao, S., Yang, Y., Zhao, X., Fan, Y., Ma, W., … Yu, Y. ( 2018 ). Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway. Oncology Reports, 39 ( 3 ), 1523 – 1531. https://doi.org/10.3892/or.2018.6188
dc.identifier.citedreferenceLiu, L. D., Pang, Y. X., Zhao, X. R., Li, R., Jin, C. J., Xue, J., … Liu, P. S. ( 2019 ). Curcumin induces apoptotic cell death and protective autophagy by inhibiting AKT/mTOR/p70S6K pathway in human ovarian cancer cells. Archives of Gynecology and Obsterics, 299 ( 6 ), 1627 – 1639. https://doi.org/10.1007/s00404-019-05058-3
dc.identifier.citedreferenceMartiny‐Baron, G., & Fabbro, D. ( 2007 ). Classical PKC isoforms in cancer. Pharmacological Research, 55 ( 6 ), 477 – 486. https://doi.org/10.1016/j.phrs.2007.04.001
dc.identifier.citedreferenceMurugan, A. K. ( 2019 ). mTOR: Role in cancer, metastasis and drug resistance. Seminars in Cancer Biology, 59, 92 – 111. https://doi.org/10.1016/j.semcancer.2019.07.003
dc.identifier.citedreferenceNelson, K. M., Dahlin, J. L., Bisson, J., Graham, J., Pauli, G. F., & Walters, M. A. ( 2017 ). The essential medicinal chemistry of curcumin. Journal of Medicinal Chemistry, 60 ( 5 ), 1620 – 1637. https://doi.org/10.1021/acs.jmedchem.6b00975
dc.identifier.citedreferenceNiero, E. L., & Machado‐Santelli, G. M. ( 2013 ). Cinnamic acid induces apoptotic cell death and cytoskeleton disruption in human melanoma cells. Journal of Experimental & Clinical Cancer Research, 32, 31. https://doi.org/10.1186/1756-9966-32-31
dc.identifier.citedreferenceNormando, A. G. C., de Meneses, A. G., de Toledo, I. P., Borges, G. A., de Lima, C. L., Dos Reis, P. E. D., & Guerra, E. N. S. ( 2019 ). Effects of turmeric and curcumin on oral mucositis: A systematic review. Phytotherapy Research, 33 ( 5 ), 1318 – 1329. https://doi.org/10.1002/ptr.6326
dc.identifier.citedreferenceEdwards, R. L., Luis, P. B., Varuzza, P. V., Joseph, A. I., Presley, S. H., Chaturvedi, R., & Schneider, C. ( 2017 ). The anti‐inflammatory activity of curcumin is mediated by its oxidative metabolites. The Journal of Biological Chemistry, 292 ( 52 ), 21243–21252. https://doi.org/10.1074/jbc.RA117.000123
dc.identifier.citedreferencePagano, E., Romano, B., Izzo, A. A., & Borrelli, F. ( 2018 ). The clinical efficacy of curcumin‐containing nutraceuticals: An overview of systematic reviews. Pharmacological Research, 134, 79 – 91. https://doi.org/10.1016/j.phrs.2018.06.007
dc.identifier.citedreferenceParsons, M., & Adams, J. C. ( 2008 ). Rac regulates the interaction of fascin with protein kinase C in cell migration. Journal of Cell Science, 121 ( 17 ), 2805 – 2813. https://doi.org/10.1242/jcs.022509
dc.identifier.citedreferencePetiti, J., Rosso, V., Lo Iacono, M., Panuzzo, C., Calabrese, C., Signorino, E., … Cilloni, D. ( 2019 ). Curcumin induces apoptosis in JAK2‐mutated cells by the inhibition of JAK2/STAT and mTORC1 pathways. Journal of Cellular and Molecular Medicine, 23 ( 6 ), 4349 – 4357. https://doi.org/10.1111/jcmm.14326
dc.identifier.citedreferencePoon, I. K., Hulett, M. D., & Parish, C. R. ( 2010 ). Molecular mechanisms of late apoptotic/necrotic cell clearance. Cell Death and Differentiation, 17 ( 3 ), 381 – 397. https://doi.org/10.1038/cdd.2009.195
dc.identifier.citedreferenceRosenberg, M., & Ravid, S. ( 2006 ). Protein kinase Cgamma regulates myosin IIB phosphorylation, cellular localization, and filament assembly. Molecular Biology of the Cell, 17 ( 3 ), 1364 – 1374. https://doi.org/10.1091/mbc.e05-07-0597
dc.identifier.citedreferenceSaadipoor, A., Razzaghdoust, A., Simforoosh, N., Mahdavi, A., Bakhshandeh, M., Moghadam, M., … Mofid, B. ( 2019 ). Randomized, double‐blind, placebo‐controlled phase II trial of nanocurcumin in prostate cancer patients undergoing radiotherapy. Phytotherapy Research, 33 ( 2 ), 370 – 378. https://doi.org/10.1002/ptr.6230
dc.identifier.citedreferenceSvitkina, T. M. ( 2018 ). Ultrastructure of the Actin cytoskeleton. Current Opinion in Cell Biology, 54, 1 – 8. https://doi.org/10.1016/j.ceb.2018.02.007
dc.identifier.citedreferenceWillenbacher, E., Khan, S. Z., Mujica, S. C. A., Trapani, D., Hussain, S., Wolf, D., & Seeber, A. ( 2019 ). Curcumin: New insights into an ancient ingredient against cancer. International Journal of Molecular Sciences, 20 ( 8 ), 1808. https://doi.org/10.3390/ijms20081808
dc.identifier.citedreferenceYoon, M. S., Rosenberger, C. L., Wu, C., Truong, N., Sweedler, J. V., & Chen, J. ( 2015 ). Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid. Molecular Cell, 58 ( 3 ), 549 – 556. https://doi.org/10.1016/j.molcel.2015.03.028
dc.identifier.citedreferenceZhang, Q., Wang, D., Singh, N. K., Kundumani‐Sridharan, V., Gadiparthi, L., Rao, C. M., & Rao, G. N. ( 2011 ). Activation of cytosolic phospholipase A2 downstream of the Src‐phospholipase D1 (PLD1)‐protein kinase C gamma (PKCgamma) signaling axis is required for hypoxia‐induced pathological retinal angiogenesis. The Journal of Biological Chemistry, 286 ( 25 ), 22489–22498. https://doi.org/10.1074/jbc.M110.217786
dc.identifier.citedreferenceZhang, Y., Chen, X., Gueydan, C., & Han, J. ( 2018 ). Plasma membrane changes during programmed cell deaths. Cell Research, 28 ( 1 ), 9 – 21. https://doi.org/10.1038/cr.2017.133
dc.identifier.citedreferenceAdibian, M., Hodaei, H., Nikpayam, O., Sohrab, G., Hekmatdoost, A., & Hedayati, M. ( 2019 ). The effects of curcumin supplementation on high‐sensitivity C‐reactive protein, serum adiponectin, and lipid profile in patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled trial. Phytotherapy Research, 33 ( 5 ), 1374 – 1383. https://doi.org/10.1002/ptr.6328
dc.identifier.citedreferenceBaffi, T. R., Van, A. N., Zhao, W., Mills, G. B., & Newton, A. C. ( 2019 ). Protein kinase C quality control by phosphatase PHLPP1 unveils loss‐of‐function mechanism in cancer. Molecular Cell, 74 ( 2 ), 378 – 392. https://doi.org/10.1016/j.molcel.2019.02.018
dc.identifier.citedreferenceBorges, G. A., Rego, D. F., Assad, D. X., Coletta, R. D., De Luca Canto, G., & Guerra, E. N. ( 2017 ). In vivo and in vitro effects of curcumin on head and neck carcinoma: A systematic review. Journal of Oral Pathology and Medicine, 46 ( 1 ), 3 – 20. https://doi.org/10.1111/jop.12455
dc.identifier.citedreferenceBray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. ( 2018 ). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68 ( 6 ), 394 – 424. https://doi.org/10.3322/caac.21492
dc.identifier.citedreferenceBrown, H. A., Thomas, P. G., & Lindsley, C. W. ( 2017 ). Targeting phospholipase D in cancer, infection and neurodegenerative disorders. Nature Reviews Drug Discovery, 16 ( 5 ), 351 – 367. https://doi.org/10.1038/nrd.2016.252
dc.identifier.citedreferenceChen, Q., Lu, G., Wang, Y., Xu, Y., Zheng, Y., Yan, L., … Zhou, J. ( 2009 ). Cytoskeleton disorganization during apoptosis induced by curcumin in A549 lung adenocarcinoma cells. Planta Medica, 75 ( 8 ), 808 – 813. https://doi.org/10.1055/s-0029-1185399
dc.identifier.citedreferenceCheng, A. L., Hsu, C. H., Lin, J. K., Hsu, M. M., Ho, Y. F., Shen, T. S., … Hsieh, C. Y. ( 2001 ). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high‐risk or pre‐malignant lesions. Anticancer Research, 21 ( 4B ), 2895 – 2900.
dc.identifier.citedreferenceCicero, A. F. G., Sahebkar, A., Fogacci, F., Bove, M., Giovannini, M., & Borghi, C. ( 2019 ). Effects of phytosomal curcumin on anthropometric parameters, insulin resistance, cortisolemia and non‐alcoholic fatty liver disease indices: A double‐blind, placebo‐controlled clinical trial. European Journal of Nutrition, 59, 477 – 483. https://doi.org/10.1007/s00394-019-01916-7
dc.identifier.citedreferenceCramer, J. D., Burtness, B., Le, Q. T., & Ferris, R. L. ( 2019 ). The changing therapeutic landscape of head and neck cancer. Nature Reviews. Clinical Oncology, 16 ( 11 ), 669 – 683. https://doi.org/10.1038/s41571-019-0227-z
dc.identifier.citedreferenceDiaz‐Moralli, S., Tarrado‐Castellarnau, M., Miranda, A., & Cascante, M. ( 2013 ). Targeting cell cycle regulation in cancer therapy. Pharmacology & Therapeutics, 138 ( 2 ), 255 – 271. https://doi.org/10.1016/j.pharmthera.2013.01.011
dc.identifier.citedreferenceDowling, C. M., Hayes, S. L., Phelan, J. J., Cathcart, M. C., Finn, S. P., Mehigan, B., … Kiely, P. A. ( 2017 ). Expression of protein kinase C gamma promotes cell migration in colon cancer. Oncotarget, 8 ( 42 ), 72096–72107. https://doi.org/10.18632/oncotarget.18916
dc.identifier.citedreferenceDowling, C. M., Phelan, J., Callender, J. A., Cathcart, M. C., Mehigan, B., McCormick, P., … Kiely, P. A. ( 2016 ). Protein kinase C beta II suppresses colorectal cancer by regulating IGF‐1 mediated cell survival. Oncotarget, 7 ( 15 ), 20919–20933. https://doi.org/10.18632/oncotarget.8062
dc.identifier.citedreferenceFife, C. M., McCarroll, J. A., & Kavallaris, M. ( 2014 ). Movers and shakers: Cell cytoskeleton in cancer metastasis. British Journal of Pharmacology, 171 ( 24 ), 5507 – 5523. https://doi.org/10.1111/bph.12704
dc.identifier.citedreferenceGarczarczyk, D., Szeker, K., Galfi, P., Csordas, A., & Hofmann, J. ( 2010 ). Protein kinase Cgamma in colon cancer cells: Expression, Thr514 phosphorylation and sensitivity to butyrate‐mediated upregulation as related to the degree of differentiation. Chemico‐Biological Interactions, 185 ( 1 ), 25 – 32. https://doi.org/10.1016/j.cbi.2010.02.035
dc.owningcollnameInterdisciplinary and Peer-Reviewed


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