{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:10:03Z","timestamp":1790971803527,"version":"4.1.0"},"reference-count":104,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Recovery and Resilience Plan"},{"name":"European Union\u2014Next Generation EU","award":["CN00000041"],"award-info":[{"award-number":["CN00000041"]}]},{"name":"European Union\u2014Next Generation EU","award":["B93D21010860004"],"award-info":[{"award-number":["B93D21010860004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background:\u00a0Malva sylvestris (the common mallow) is an herbaceous species widely used in ethnobotanical practices to treat gastrointestinal, hepatic and urinary inflammation. Objectives: Despite these beneficial effects on human health, the antineoplastic potential of this plant has not yet been fully explored. Thus, in the present study, two human colon cancer cell lines (i.e., HCT-116 and Caco-2) were treated with an extract obtained from M. sylvestris flowers (MFE), whose composition in terms of phytochemicals and microRNAs has been recently published by our research group, to explore its potential bioactivity. Methods\/Results: MTT and Trypan blue assays demonstrated that MFE reduced tumour cell growth without causing significant cytotoxicity or apoptosis. Following the diphenylboric acid 2-aminoethyl ester-induced fluorescence of some plant metabolites, microscopy analysis proved that MFE components crossed the cell membranes, accumulating into nuclei. Wound assay and transwell tests documented that MFE was also able to reduce cell motility and invasiveness. In both cell lines qPCR experiments demonstrated that MFE caused the over-expression of factors, like VIMENTIN and E-CADHERIN, which negatively influence epithelial\u2013mesenchymal transition in colon cancers. However, the effects of MFE appeared to be time-, dose- and cell type-dependent. In fact, the treatment induced senescence in P53-null Caco-2 cells (i.e., ROS, \u03b2-galactosidase and P21WAF1\/Cip1) and a premise of differentiation (i.e., P27Kip1) in P53-wild-type HCT-116 cells, also via the CDK2\/c-MYC\/AKT axis, justifying its antiproliferative property. In parallel, the transfection of tumour cells with pure synthetic miR160b-5p\u2014a microRNA identified in M. sylvestris flowers and predicted to target the human CDK2 transcript\u2014resulted in gene silencing, thereby suggesting its central role in mediating the cross-kingdom effects of MFE on the investigated cancer models. Conclusions: Overall, these findings open new perspectives on the common mallow as a source of potential antimetastatic compounds and on the possible use of its plant microRNAs in the development of gene therapies.<\/jats:p>","DOI":"10.3390\/nu18030495","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T15:38:12Z","timestamp":1770046692000},"page":"495","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Malva sylvestris Flower Extract Exhibits Antineoplastic Potential Against Human Colon Cancer Cell Lines and Induces CDK2 Transcript Instability via Plant miR160-5p"],"prefix":"10.3390","volume":"18","author":[{"given":"Valentina","family":"Villani","sequence":"first","affiliation":[{"name":"Laboratory of Botany, Department Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica 1, 00133 Rome, Italy"},{"name":"PhD Programme in Molecular and Cellular Biology, Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9257-9667","authenticated-orcid":false,"given":"Angelo","family":"Gismondi","sequence":"additional","affiliation":[{"name":"Laboratory of Botany, Department Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Vijayakumar, R., and Raja, S. (2022). Plant secondary metabolites: Therapeutic potential and pharmacological properties. Secondary Metabolites\u2014Trends and Reviews, IntechOpen.","DOI":"10.5772\/intechopen.98129"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5395","DOI":"10.1021\/jm030956v","article-title":"Anticancer activity of phenolic acids of natural or synthetic origin: A structure\u2013activity study","volume":"46","author":"Gomes","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kopustinskiene, D.M., Jakstas, V., Savickas, A., and Bernatoniene, J. (2020). Flavonoids as anticancer agents. Nutrients, 12.","DOI":"10.3390\/nu12020457"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhang, N., Ying, M.D., Wu, Y.P., Zhou, Z.H., Ye, Z.M., Li, H., and Lin, D.S. (2014). Hyperoside inhibits proliferation and stimulates osteogenic differentiation of human osteosarcoma cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098973"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phymed.2018.06.008","article-title":"Hydroalcoholic extract of Spartium junceum L. flowers inhibits growth and melanogenesis in B16-F10 cells by inducing senescence","volume":"46","author":"Nanni","year":"2018","journal-title":"Phytomedicine"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Forni, C., Rossi, M., Borromeo, I., Feriotto, G., Platamone, G., Tabolacci, C., and Beninati, S. (2021). Flavonoids: A myth or a reality for cancer therapy?. Molecules, 26.","DOI":"10.3390\/molecules26123583"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ponte, L.G.S., Pavan, I.C.B., Mancini, M.C.S., da Silva, L.G.S., Morelli, A.P., Severino, M.B., and Simabuco, F.M. (2021). The hallmarks of flavonoids in cancer. Molecules, 26.","DOI":"10.3390\/molecules26072029"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1017\/jns.2016.41","article-title":"Flavonoids: An overview","volume":"5","author":"Panche","year":"2016","journal-title":"J. Nutr. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1080\/10408398.2018.1437023","article-title":"Polyphenols and bioavailability: An update","volume":"59","author":"Teng","year":"2019","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/s42003-019-0563-7","article-title":"Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts","volume":"2","author":"Aquilano","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s11033-020-06070-6","article-title":"Plant miR171 modulates mTOR pathway in HEK293 cells by targeting GNA12","volume":"48","author":"Gismondi","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s43094-022-00413-9","article-title":"Recent trends in miRNA therapeutics and application of plant miRNA for prevention and treatment of human diseases","volume":"8","author":"Saiyed","year":"2022","journal-title":"Future J. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1055\/s-0042-108450","article-title":"MicroRNAs as new bioactive components in medicinal plants","volume":"82","author":"Xie","year":"2016","journal-title":"Planta Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1080\/15476286.2018.1551693","article-title":"Dietary plant miRNAs as an augmented therapy: Cross-kingdom gene regulation","volume":"15","author":"Sanchita","year":"2018","journal-title":"RNA Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.biomaterials.2019.04.033","article-title":"Plant-derived RNAi therapeutics: A strategic inhibitor of HBsAg","volume":"210","author":"Zhang","year":"2019","journal-title":"Biomaterials"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/j.2042-7158.2011.01383.x","article-title":"Ethnobotanical and scientific aspects of Malva sylvestris L.: A millennial herbal medicine","volume":"64","author":"Gasparetto","year":"2012","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.biopha.2017.06.083","article-title":"Preclinical efficacy assessment of Malva sylvestris on chronic skin inflammation","volume":"93","author":"Prudente","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.hermed.2018.01.005","article-title":"Combination of Malva sylvestris and Althaea digitata for prevention of acute radiation proctitis","volume":"12","author":"Moeini","year":"2018","journal-title":"J. Herb. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s00210-022-02329-w","article-title":"Phytochemical profiling, pharmacological activities, and safety of Malva sylvestris: A review","volume":"396","author":"Batiha","year":"2023","journal-title":"Naunyn-Schmiedebergs Arch. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Villani, V., Di Marco, G., Iacovelli, F., Pietrucci, D., Canini, A., and Gismondi, A. (2023). Profile and potential bioactivity of the miRNome and metabolome of Malva sylvestris leaf and flower. BMC Plant Biol., 23.","DOI":"10.1186\/s12870-023-04434-1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1080\/00087114.2007.10589552","article-title":"Identification of phenolic compounds from medicinal and melliferous plants and their cytotoxic activity in cancer cells","volume":"60","author":"Alesiani","year":"2007","journal-title":"Caryologia"},{"key":"ref_22","first-page":"70","article-title":"Cytotoxicity assessment of Malva sylvestris crude extract on melanoma and lymphoma cell lines","volume":"11","author":"Rayssan","year":"2019","journal-title":"J. Pharm. Sci. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3325","DOI":"10.1016\/j.fct.2008.08.004","article-title":"Antiproliferative activity against human tumor cell lines and toxicity test on Mediterranean dietary plants","volume":"46","author":"Conforti","year":"2008","journal-title":"Food Chem. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/newbio242148a0","article-title":"Selection of successive tumour lines for metastasis","volume":"242","author":"Fidler","year":"1973","journal-title":"Nat. New Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s10068-014-0010-y","article-title":"Rapid quantification of cellular flavonoid levels using quercetin and a fluorescent diphenylboric acid 2-aminoethyl ester probe","volume":"23","author":"Lee","year":"2014","journal-title":"Food Sci. Biotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1177\/1087057116653220","article-title":"Flow cytometric method for the detection of flavonoids in cell lines","volume":"21","author":"Grootaert","year":"2016","journal-title":"J. Biomol. Screen."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"D\u2019Agostino, A., Di Marco, G., Canini, A., and Gismondi, A. (2025). Megagametophyte maturation dynamics and flavonol changes during Arbutus unedo flower development. Front. Plant Sci., 16.","DOI":"10.3389\/fpls.2025.1694629"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gismondi, A., Di Marco, G., and Canini, A. (2017). Detection of plant microRNAs in honey. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172981"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1007\/s00344-022-10686-2","article-title":"MicroRNA expression profiles in Moringa oleifera seedlings under different growth conditions","volume":"42","author":"Gismondi","year":"2023","journal-title":"J. Plant Growth Regul."},{"key":"ref_30","first-page":"1905","article-title":"Role of nutrition in preventing cancer","volume":"53","author":"Gingras","year":"2007","journal-title":"Can. Fam. Physician"},{"key":"ref_31","first-page":"264","article-title":"Efficacy of Terminalia arjuna on N-nitrosodiethylamine-induced hepatocellular carcinoma in rats","volume":"43","author":"Sivalokanathan","year":"2005","journal-title":"Indian J. Exp. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.2174\/1568026619666181224101132","article-title":"Prospective plant-based anticancer lead molecules","volume":"18","author":"Kaur","year":"2019","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.1007\/s13197-018-3330-8","article-title":"Botanical influence on phenolic profile and antioxidant level of Italian honeys","volume":"55","author":"Gismondi","year":"2018","journal-title":"J. Food Sci. Technol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0168-9452(01)00490-3","article-title":"Production of plant secondary metabolites: A historical perspective","volume":"161","author":"Bourgaud","year":"2001","journal-title":"Plant Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.foodchem.2011.01.003","article-title":"LC-DAD-ESI\/MS analysis of flavonoids and abscisic acid for classification of Slovenian honey","volume":"127","author":"Bertoncelj","year":"2007","journal-title":"Food Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1038\/nrc1189","article-title":"Cancer chemoprevention with dietary phytochemicals","volume":"3","author":"Surh","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural products as sources of new drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_38","unstructured":"Egbuna, C., Kumar, S., Ifemeje, J., Ezzat, S., and Kaliyaperumal, S. (2020). Plant secondary metabolites as lead compounds. Phytochemicals as Lead Compounds for New Drug Discovery, Elsevier."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jep.2005.05.011","article-title":"Plants as a source of anti-cancer agents","volume":"100","author":"Cragg","year":"2005","journal-title":"J. Ethnopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.drudis.2015.01.009","article-title":"An analysis of FDA-approved drugs: Natural products and derivatives","volume":"21","author":"Patridge","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Thomford, N., Senthebane, D., Rowe, A., Munro, D., Seele, P., Maroyi, A., and Dzobo, K. (2018). Natural products for drug discovery in the 21st century. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061578"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4667","DOI":"10.18203\/2320-6012.ijrms20174914","article-title":"Colorectal cancer: A review","volume":"5","year":"2017","journal-title":"Int. J. Res. Med. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3522","DOI":"10.1080\/10408398.2019.1699014","article-title":"Effects of phytochemicals on cellular signaling","volume":"60","author":"Pham","year":"2020","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Khan, A.W., Farooq, M., Haseeb, M., and Choi, S. (2022). Role of plant-derived constituents in cancer treatment. Cells, 11.","DOI":"10.3390\/cells11081326"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lyubitelev, A., and Studitsky, V. (2023). Inhibition of cancer development by plant polyphenols. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310663"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Majrashi, T.A., Alshehri, S.A., Alsayari, A., Muhsinah, A.B., Alrouji, M., Alshahrani, A.M., and Atiya, A. (2023). Phytochemicals in cancer therapeutics. Nutrients, 15.","DOI":"10.3390\/nu15071704"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1002\/fsn3.3308","article-title":"Phytobioactive compounds as therapeutic agents","volume":"11","author":"Riaz","year":"2023","journal-title":"Food Sci. Nutr."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Atrahimovich, D., Avni, D., and Khatib, S. (2021). Flavonoids\u2013macromolecule interactions in human diseases. Antioxidants, 10.","DOI":"10.3390\/antiox10030423"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1007\/s11064-008-9697-6","article-title":"Role of nitric oxide synthases in Parkinson\u2019s disease","volume":"33","author":"Aquilano","year":"2008","journal-title":"Neurochem. Res."},{"key":"ref_50","first-page":"73","article-title":"Nutrients and phytochemicals: From bioavailability to bioefficacy","volume":"19","author":"Holst","year":"2008","journal-title":"Food Biotechnol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"228","DOI":"10.4161\/oxim.3.4.12858","article-title":"Exogenous antioxidants: Double-edged swords","volume":"3","author":"Bouayed","year":"2010","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"20175","DOI":"10.1016\/S0021-9258(18)54906-1","article-title":"Covalent modification of guanine bases in DNA","volume":"266","author":"Kagawa","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_53","first-page":"1","article-title":"How mitochondria produce reactive oxygen species","volume":"417","author":"Murphy","year":"2008","journal-title":"Biochem. J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s12013-011-9303-4","article-title":"Prooxidant action of dietary antioxidants","volume":"67","author":"Ullah","year":"2011","journal-title":"Cell Biochem. Biophys."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1080\/15216540252774694","article-title":"Reactive oxygen species and signal transduction","volume":"52","author":"Finkel","year":"2001","journal-title":"IUBMB Life"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s12943-019-0961-y","article-title":"Reactive oxygen species in cancerization","volume":"18","author":"Liao","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1080\/15384101.2014.1000134","article-title":"Senescence from G2 arrest revisited","volume":"14","author":"Gire","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1161\/CIRCRESAHA.111.247866","article-title":"Assessing senescence biomarkers","volume":"111","author":"Blasco","year":"2012","journal-title":"Circ. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/nrm1490","article-title":"Integrin signalling during tumour progression","volume":"5","author":"Guo","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.bbrc.2011.02.002","article-title":"Unconventional actin conformations in mitosis","volume":"406","author":"Hubert","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_61","first-page":"408","article-title":"Vimentin expression in hepatocellular carcinoma","volume":"30","author":"Li","year":"2008","journal-title":"Chin. J. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1007\/s00018-011-0735-1","article-title":"Vimentin in cancer","volume":"68","author":"Satelli","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_63","first-page":"121","article-title":"Roles of cadherins in cancer","volume":"14","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc2748","article-title":"Integrins in cancer","volume":"10","author":"Desgrosellier","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.tcb.2014.12.006","article-title":"Integrins and cancer stemness","volume":"25","author":"Seguin","year":"2015","journal-title":"Trends Cell Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1080\/15384101.2017.1316573","article-title":"Integrins in senescence and aging","volume":"16","author":"Borghesan","year":"2017","journal-title":"Cell Cycle"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1016\/j.celrep.2017.02.012","article-title":"Integrin \u03b23 regulates senescence via TGF-\u03b2","volume":"18","author":"Rapisarda","year":"2017","journal-title":"Cell Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1073\/pnas.96.5.2147","article-title":"p53 regulates a G2 checkpoint","volume":"96","author":"Innocente","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","first-page":"4285","article-title":"Characterization of the p53 pathway","volume":"57","author":"Jackman","year":"1997","journal-title":"Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10495-010-0538-0","article-title":"Mdm2 inhibition induces apoptosis in p53-deficient cells","volume":"16","author":"Ray","year":"2011","journal-title":"Apoptosis"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/ng0695-175","article-title":"p53-deficient embryos and exencephaly","volume":"10","author":"Sah","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_72","first-page":"a001040","article-title":"p53 regulation of metabolic pathways","volume":"2","author":"Gottlieb","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1038\/cdd.2011.12","article-title":"HAUSP-mediated p53 regulation","volume":"18","author":"Kon","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nrm3086","article-title":"The p53 family","volume":"12","author":"Levine","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s00109-011-0766-y","article-title":"ARF\/p53-independent senescence pathways","volume":"89","author":"Chan","year":"2011","journal-title":"J. Mol. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/ncomms1473","article-title":"Senescence independent of p53 and p16","volume":"2","author":"Prieur","year":"2011","journal-title":"Nat. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5129","DOI":"10.1038\/onc.2012.640","article-title":"Senescence and aging","volume":"32","author":"Rufini","year":"2013","journal-title":"Oncogene"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.bbamcr.2008.01.008","article-title":"Induction of p21 in p53-null cells","volume":"1783","author":"Ma","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/ncb2070","article-title":"CCN1 induces fibroblast senescence","volume":"12","author":"Jun","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.cellsig.2015.01.005","article-title":"Sp1 regulates p21CIP1 transcription","volume":"27","author":"Karkhanis","year":"2015","journal-title":"Cell. Signal."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/12013","article-title":"SKP2-mediated degradation of p27","volume":"1","author":"Carrano","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6959","DOI":"10.1038\/s41467-021-27124-8","article-title":"NUCKS1\u2013SKP2\u2013p21\/p27 axis","volume":"12","author":"Hume","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"391","DOI":"10.4161\/cc.1.6.262","article-title":"p27 and p21 as cytoplasmic oncoproteins","volume":"1","author":"Blagosklonny","year":"2002","journal-title":"Cell Cycle"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.dnarep.2018.07.008","article-title":"Multiple functions of p27","volume":"69","author":"Abbastabar","year":"2018","journal-title":"DNA Repair"},{"key":"ref_85","first-page":"25","article-title":"p27KIP1 maintains terminal differentiation","volume":"5","author":"Kil","year":"2011","journal-title":"Open Otolaryngol. J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.devcel.2015.10.014","article-title":"Connexin controls cell-cycle exit","volume":"35","author":"Shi","year":"2015","journal-title":"Dev. Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1002\/jcp.20750","article-title":"Cell senescence beyond the restriction point","volume":"209","author":"Blagosklonny","year":"2006","journal-title":"J. Cell Physiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1002\/bies.200900005","article-title":"Switching AKT signaling","volume":"31","author":"Los","year":"2009","journal-title":"BioEssays"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/ncb0110-7","article-title":"Myc and Cdk2 senescence switch","volume":"12","author":"Felsher","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/344503a0","article-title":"Universal control mechanism of M-phase","volume":"344","author":"Nurse","year":"1990","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"106","DOI":"10.5483\/BMBRep.2002.35.1.106","article-title":"AKT: Versatile mediator of cell survival","volume":"35","author":"Kim","year":"2002","journal-title":"BMB Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"244","DOI":"10.18632\/aging.100140","article-title":"Cdk2 regulation of Myc-induced senescence","volume":"2","author":"Hydbring","year":"2010","journal-title":"Aging"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1210\/en.2013-1929","article-title":"Akt inactivation induces senescence","volume":"155","author":"Xu","year":"2014","journal-title":"Endocrinology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.canlet.2019.02.004","article-title":"Dual Akt and ERK inhibition induces senescence","volume":"448","author":"He","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1038\/sj.onc.1203541","article-title":"c-Myc antagonizes p53 effects","volume":"19","author":"Ceballos","year":"2000","journal-title":"Oncogene"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.1017\/S1462399408000744","article-title":"p21 and p27 in carcinogenesis","volume":"10","author":"Abukhdeir","year":"2008","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"28706","DOI":"10.1074\/jbc.M203668200","article-title":"Akt-dependent phosphorylation of p27Kip1","volume":"277","author":"Fujita","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"26759","DOI":"10.1074\/jbc.M703229200","article-title":"Resveratrol-induced senescence","volume":"282","author":"Heiss","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/S0531-5565(02)00133-X","article-title":"RAF\/MEK\/ERK and PI3K\/AKT pathways in senescence","volume":"37","author":"Lorenzini","year":"2002","journal-title":"Exp. Gerontol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/aps.2012.42","article-title":"Roles of vimentin and 14-3-3 zeta\/delta in the inhibitory effects of heparin on PC-3M cell proliferation and B16-F10-luc-G5 cells metastasis","volume":"33","author":"Pan","year":"2012","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"6550","DOI":"10.1128\/MCB.24.15.6550-6559.2004","article-title":"The microphthalmia transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: Link between melanin synthesis and melanosome biogenesis","volume":"24","author":"Vetrini","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"30008","DOI":"10.18632\/oncotarget.15611","article-title":"OSR1 is a novel epigenetic silenced tumor suppressor regulating invasion and proliferation in renal cell carcinoma","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"462","DOI":"10.7150\/ijms.18154","article-title":"Induction of mitotic delay in pharyngeal and nasopharyngeal carcinoma cells using an aqueous extract of Ajuga bracteosa","volume":"14","author":"Lin","year":"2017","journal-title":"Int. J. Med. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"7353","DOI":"10.1128\/MCB.20.19.7353-7362.2000","article-title":"Control of hnRNP A1 alternative splicing: An intron element represses use of the common 3\u2032 splice site","volume":"20","author":"Simard","year":"2000","journal-title":"Mol. Cell. Biol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/3\/495\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T15:45:29Z","timestamp":1770047129000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/3\/495"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,2]]},"references-count":104,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["nu18030495"],"URL":"https:\/\/doi.org\/10.3390\/nu18030495","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,2]]}}}