{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T22:55:14Z","timestamp":1776898514738,"version":"3.51.2"},"reference-count":91,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Meningiomas are the most frequent primary tumors arising in the central nervous system. They typically follow a benign course, with an excellent prognosis for grade I lesions through surgical intervention. Although radiotherapy is a good option for recurrent, progressive, or inoperable tumors, alternative treatments are very limited. mTOR is a protein complex with increasing therapeutical potential as a target in cancer. The current understanding of the mTOR pathway heavily involves it in the development of meningioma. Its activation is strongly dependent on PI3K\/Akt signaling and the merlin protein. Both factors are commonly defective in meningioma cells, which indicates their likely function in tumor growth. Furthermore, regarding molecular tumorigenesis, the kinase activity of the mTORC1 complex inhibits many components of the autophagosome, such as the ULK1 or Beclin complexes. mTOR contributes to redox homeostasis, a vital component of neoplasia. Recent clinical trials have investigated novel chemotherapeutic agents for mTOR inhibition, showing promising results in resistant or recurrent meningiomas.<\/jats:p>","DOI":"10.3390\/ijms23041978","type":"journal-article","created":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T02:35:51Z","timestamp":1644546951000},"page":"1978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["mTOR Signaling and Potential Therapeutic Targeting in Meningioma"],"prefix":"10.3390","volume":"23","author":[{"given":"Benjamin","family":"Pinker","sequence":"first","affiliation":[{"name":"Medical Faculty, Karol Marcinkowski University of Medical Sciences, Fredry 10, 61-701 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7179-1474","authenticated-orcid":false,"given":"Anna-Maria","family":"Barciszewska","sequence":"additional","affiliation":[{"name":"Intraoperative Imaging Unit, Chair and Department of Neurosurgery and Neurotraumatology, Karol Marcinkowski University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland"},{"name":"Department of Neurosurgery and Neurotraumatology, Heliodor Swiecicki Clinical Hospital, Przybyszewskiego 49, 60-355 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iii1","DOI":"10.1093\/neuonc\/noab200","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014\u20132018","volume":"23","author":"Ostrom","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1080\/02688697.2019.1661965","article-title":"The outcome of patients with surgically treated meningioma in England: 1999\u20132013. A cancer registry data analysis","volume":"33","author":"Brodbelt","year":"2019","journal-title":"Br. J. Neurosurg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO Classification of Tumors of the Central Nervous System: A summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1093\/neuonc\/nos013","article-title":"Impaired survival and long-term neurological problems in benign meningioma","volume":"14","author":"Dieleman","year":"2012","journal-title":"Neuro-Oncology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.ijrobp.2011.08.010","article-title":"Long-term outcome after radiotherapy in patients with atypical and malignant meningiomas\u2013clinical results in 85 patients treated in a single institution leading to optimized guidelines for early radiation therapy","volume":"83","author":"Adeberg","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"876","DOI":"10.3171\/2017.11.JNS172278","article-title":"Surgical outcomes after reoperation for recurrent skull base meningiomas","volume":"130","author":"Magil","year":"2018","journal-title":"J. Neurosurg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1055\/s-0033-1354747","article-title":"Review of Stereotactic Radiosurgery Practice in the Management of Skull Base Meningiomas","volume":"75","author":"Vera","year":"2014","journal-title":"J. Neurol. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2015\/320941","article-title":"Blood Brain Barrier: A Challenge for Effectual Therapy of Brain Tumors","volume":"2015","author":"Bhowmik","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kim, L. (2020). A narrative review of targeted therapies in meningioma. Chin. Clin. Oncol., 9.","DOI":"10.21037\/cco-2020-mbt-01"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1158\/1078-0432.CCR-19-2109","article-title":"Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial","volume":"26","author":"Graillon","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Falzone, L., Salomone, S., and Libra, M. (2018). Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01300"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tian, T., Li, X., and Zhang, J. (2019). mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030755"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zou, Z., Tao, T., Li, H., and Zhu, X. (2020). mTOR signaling pathway and mTOR inhibitors in cancer: Progress and challenges. Cell Biosci., 10.","DOI":"10.1186\/s13578-020-00396-1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13045-019-0754-1","article-title":"Targeting mTOR for cancer therapy","volume":"12","author":"Hua","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Popova, N., and J\u00fccker, M. (2021). The Role of mTOR Signaling as a Therapeutic Target in Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041743"},{"key":"ref_16","unstructured":"U.S. Food & Drug Administrtation (2021, December 31). Search Orphan Drug Designations and Approvals, Available online: https:\/\/www.accessdata.fda.gov\/scripts\/opdlisting\/oopd\/detailedIndex.cfm?cfgridkey=379312."},{"key":"ref_17","unstructured":"U.S. Food & Drug Administrtation (2021, December 31). Search Orphan Drug Designations and Approvals, Available online: https:\/\/www.accessdata.fda.gov\/scripts\/opdlisting\/oopd\/detailedIndex.cfm?cfgridkey=196404."},{"key":"ref_18","unstructured":"Drugs.com (2021, December 31). Afinitor FDA Approval History. Available online: https:\/\/www.drugs.com\/history\/afinitor.html."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4250","DOI":"10.1128\/MCB.01581-08","article-title":"NF2\/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth","volume":"29","author":"James","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/ng.2526","article-title":"Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations","volume":"45","author":"Brastianos","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1158\/1078-0432.CCR-12-1904","article-title":"mTORC1 inhibitors suppress meningioma growth in mouse models","volume":"19","author":"Pachow","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.tcb.2007.03.006","article-title":"Shedding light on Merlin\u2019s wizardry","volume":"17","author":"Okada","year":"2007","journal-title":"Trends Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1083\/jcb.200503165","article-title":"Merlin\/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane","volume":"171","author":"Okada","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1101\/gad.189601","article-title":"The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44","volume":"15","author":"Morrison","year":"2001","journal-title":"Genes Dev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s12307-018-0216-2","article-title":"Cerebrospinal Fluid Hyaluronan and Neurofibromatosis Type 2","volume":"11","author":"Ariyannur","year":"2018","journal-title":"Cancer Microenviron."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1128\/MCB.01578-08","article-title":"Loss of the Tumor Suppressor Gene NF2, Encoding Merlin, Constitutively Activates Integrin-Dependent mTORC1 Signalling","volume":"29","author":"Okada","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s11523-019-00654-4","article-title":"A Monoclonal Antibody Against \u03b21 Integrin Inhibits Proliferation and Increases Survival in an Orthotopic Model of High-Grade Meningioma","volume":"14","author":"Nigim","year":"2019","journal-title":"Target Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Shapiro, M.I., Kolev, V.N., Vidal, C.M., Kadariya, Y., Ring, J.E., Wright, Q., Weaver, D.T., Menges, C., Padval, M., and McClatchey, A. (2014). Merlin deficiency predicts for FAK inhibitor sensitivity: A synthetic lethal relationship. Sci. Transl. Med., 6.","DOI":"10.1126\/scitranslmed.3008639"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"42590","DOI":"10.18632\/oncotarget.6052","article-title":"The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications","volume":"6","author":"Sang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3533","DOI":"10.21037\/jtd.2017.09.34","article-title":"Essential signaling in NF2 loss-related tumours: The therapeutic potential of CRL4DCAF1 and mTOR combined inhibition","volume":"9","author":"Yang","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kma, L., and Baruah, T.J. (2021). The interplay of ROS and the PI3K\/Akt pathway in autophagy regulation. Biotechnol. Appl. Biochem.","DOI":"10.1002\/bab.2104"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.3390\/ijms13021886","article-title":"The mTOR signalling pathway in human cancer","volume":"13","author":"Lopes","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16981","DOI":"10.18632\/oncotarget.4858","article-title":"A high-throughput kinome screen reveals serum\/glucocorticoid- regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas","volume":"6","author":"Beauchamp","year":"2015","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1007\/s12250-021-00450-3","article-title":"mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication","volume":"36","author":"Wang","year":"2021","journal-title":"Virol. Sin."},{"key":"ref_35","first-page":"605","article-title":"The PI3K pathway in human disease","volume":"170","author":"Fruman","year":"2018","journal-title":"Cell Press"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R368","DOI":"10.1016\/j.cub.2012.03.003","article-title":"Organ Size Control by Hippo and TOR Pathways","volume":"22","author":"Tumaneng","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Koundouros, N., and Poulogiannis, G. (2018). Phosphoinositide 3-Kinase\/Akt Signaling and Redox Metabolism in Cancer. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00160"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1111\/ajt.15320","article-title":"The \u201cother\u201d mTOR complex: New insights into mTORC2 immunobiology and their implications","volume":"19","author":"Dai","year":"2019","journal-title":"Am. J. Transplant."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"An, P., Xu, W., Luo, J., and Luo, Y. (2021). Expanding TOR Complex 2 Signaling: Emerging Regulators and New Connections. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.713806"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Fu, W., and Hall, M.N. (2020). Regulation of mTORC2 Signaling. Genes, 11.","DOI":"10.3390\/genes11091045"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1083\/jcb.201610060","article-title":"Localization of mTORC2 activity inside cells","volume":"216","author":"Ebner","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1158\/1541-7786.MCR-11-0425-T","article-title":"Regulation of mTOR Complex 2 Signaling in Neurofibromatosis 2-Deficient Target Cell Types","volume":"10","author":"James","year":"2012","journal-title":"Mol. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.molcel.2006.03.029","article-title":"Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt\/PKB","volume":"22","author":"Sarbassov","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_44","first-page":"239","article-title":"Safety, Efficacy, and Patient Acceptability of Everolimus in the Treatment of Breast Cancer","volume":"10","author":"Lousberg","year":"2016","journal-title":"Breast Cancer Clin. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1080\/07357907.2017.1344697","article-title":"Discontinuation of Everolimus Due to Related and Unrelated Adverse Events in Cancer Patients: A Meta-Analysis","volume":"35","author":"Rogers","year":"2017","journal-title":"Cancer Investig."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Arena, C., Bizzoca, M.E., Caponio, V.C.A., Troiano, G., Zhurakivska, K., Leuci, S., and Lo Muzio, L. (2021). Everolimus therapy and side-effects: A systematic review and meta-analysis. Int. J. Oncol., 59.","DOI":"10.3892\/ijo.2021.5234"},{"key":"ref_47","unstructured":"MedChemExpress (2021, December 31). Rapamycin. Available online: https:\/\/www.medchemexpress.com\/Rapamycin.html."},{"key":"ref_48","unstructured":"MedChemExpress (2021, December 31). Temsirolimus. Available online: https:\/\/www.medchemexpress.com\/Temsirolimus.html."},{"key":"ref_49","unstructured":"MedChemExpress (2021, December 31). Everolimus. Available online: https:\/\/www.medchemexpress.com\/Everolimus.html."},{"key":"ref_50","unstructured":"MedChemExpress (2021, December 31). Vistusertib. Available online: https:\/\/www.medchemexpress.com\/AZD2014.html."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1111\/ajt.12669","article-title":"Everolimus Inhibits Anti-HLA I Antibody-Mediated Endothelial Cell Signaling, Migration and Proliferation More Potently than Sirolimus","volume":"14","author":"Jin","year":"2014","journal-title":"Am. J. Transplant."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1042\/BJ20111451","article-title":"Autophagy, mitochondria and oxidative stress: Cross-talk and redox signalling","volume":"441","author":"Lee","year":"2012","journal-title":"Biochem. J."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Dossou, S.A., and Basu, A. (2019). The Emerging Roles of mTORC1 in Macromanaging Autophagy. Cancers, 11.","DOI":"10.3390\/cancers11101422"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s10014-015-0212-x","article-title":"High thioredoxin reductase 1 expression in meningiomas undergoing malignant progression","volume":"32","author":"Esen","year":"2015","journal-title":"Brain Tumor Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Wen, C., Wang, H., Wu, X., He, L., Zhou, Q., Wang, F., Chen, S., Huang, L., Chen, J., and Wang, H. (2019). ROS-mediated inactivation of the PI3K\/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin. Cell Death Dis., 10.","DOI":"10.1038\/s41419-019-2035-x"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e383","DOI":"10.1016\/S1470-2045(16)30321-7","article-title":"EANO guidelines for the diagnosis and treatment of meningiomas","volume":"17","author":"Goldbrunner","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41586-021-03850-3","article-title":"A clinically applicable integrative molecular classification of meningiomas","volume":"597","author":"Nassiri","year":"2021","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"668","DOI":"10.3171\/jns.2002.97.3.0668","article-title":"Evidence for phosphatidylinositol 3-kinase-Akt-p7S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells","volume":"97","author":"Johnson","year":"2002","journal-title":"J. Neurosurg."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/neuonc\/nou164","article-title":"The mTOR signaling pathway as a treatment target for intracranial neoplasms","volume":"17","author":"Pachow","year":"2015","journal-title":"Neuro-Oncology"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Mei, Y., Du, Z., Hu, C., Greenwald, N.F., Abedalthagafi, M., Agar, N.Y.R., Dunn, G.P., Bi, W.L., Santagata, S., and Dunn, I.F. (2017). Osteoglycin promotes meningioma development through downregulation of NF2 and activation of mTOR signaling. Cell Commun. Signal., 15.","DOI":"10.1186\/s12964-017-0189-7"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1158\/0008-5472.CAN-04-3137","article-title":"Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts","volume":"65","author":"Wu","year":"2005","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4181","DOI":"10.1182\/blood-2004-03-1153","article-title":"In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model","volume":"104","author":"Frost","year":"2004","journal-title":"Blood"},{"key":"ref_63","first-page":"1301","article-title":"Everolimus effectively blocks pulmonary metastases from meningioma","volume":"17","author":"Bertolini","year":"2015","journal-title":"Neuro-Oncology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s11060-016-2172-3","article-title":"A phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma","volume":"129","author":"Shih","year":"2016","journal-title":"J. Neuro-Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"660","DOI":"10.3171\/2016.8.JNS16995","article-title":"Octreotide therapy in meningiomas: In vitro study, clinical correlation, and literature review","volume":"127","author":"Graillon","year":"2017","journal-title":"J. Neurosurg."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1093\/neuonc\/nox018","article-title":"Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1\/2 activation and reduced time to tumor recurrence","volume":"19","author":"Kirches","year":"2017","journal-title":"Neuro-Oncology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/neup.12524","article-title":"High p-mTOR expression is associated with recurrence and shorter disease-free survival in atypical meningiomas","volume":"39","author":"Barresi","year":"2018","journal-title":"Neuropathology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s11060-008-9746-7","article-title":"Increased STAT-3 and synchronous activation of Raf-1-MEK-1-MAPK, and phosphatidylinositol 3-Kinase-Akt-mTOR pathways in atypical and anaplastic meningiomas","volume":"92","author":"Johnson","year":"2009","journal-title":"J. Neuro-Oncol."},{"key":"ref_69","first-page":"473","article-title":"Complex interactions between the components of the PI3K\/AKT\/mTOR pathway, and with components of MAPK, JAK\/STAT and Notch-1 pathways, indicate their involvement in meningioma development","volume":"465","author":"Levidou","year":"2014","journal-title":"Eur. J. Pathol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3090","DOI":"10.1039\/C9FO00580C","article-title":"Let food be your medicine: Nutraceutical properties of lycopene","volume":"10","author":"Grabowska","year":"2019","journal-title":"Food Funct."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Marzocco, S., Singla, R.K., and Capasso, A. (2021). Multifaceted Effects of Lycopene: A Boulevard to the Multitarget-Based Treatment for Cancer. Molecules, 26.","DOI":"10.3390\/molecules26175333"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Puah, B.P., Jalil, J., Attiq, A., and Kamisah, Y. (2021). New Insights into Molecular Mechanism behind Anti-Cancer Activities of Lycopene. Molecules, 26.","DOI":"10.3390\/molecules26133888"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.2147\/DDDT.S251614","article-title":"Lycopene Inhibits Epithelial\u2013Mesenchymal Transition and Promotes Apoptosis in Oral Cancer via PI3K\/AKT\/m-TOR Signal Pathway","volume":"14","author":"Wang","year":"2020","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Wang, H., Zhu, B., Yu, L., Li, Q., Li, S., Wang, P., Jing, T., and Men, T. (2021). Lycopene Attenuates Hypoxia-Induced Testicular Injury by Inhibiting PROK2 Expression and Activating PI3K\/AKT\/mTOR Pathway in a Varicocele Adult Rat. Evid.-Based Complement. Altern. Med.","DOI":"10.1155\/2021\/3471356"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1158\/1940-6207.CAPR-14-0154","article-title":"Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice","volume":"7","author":"Ip","year":"2014","journal-title":"Cancer Prev. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1080\/01635581.2014.894092","article-title":"Orally administered lycopene attenuates diethylnitrosamine-induced hepatocarcinogenesis in rats by modulating Nrf-2\/HO-1 and Akt\/mTOR pathways","volume":"66","author":"Sahin","year":"2014","journal-title":"Nutr. Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Pungsrinont, T., Kallenbach, J., and Baniahmad, A. (2021). Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222011088"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.3892\/ijo.2014.2601","article-title":"Targeting the PI3K\/Akt pathway in prostate cancer: Challenges and opportunities (review)","volume":"45","author":"Toren","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1002\/pros.20410","article-title":"Expression of mTOR signaling pathway markers in prostate cancer progression","volume":"66","author":"Kremer","year":"2006","journal-title":"Prostate"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1002\/1097-0142(19890801)64:3<605::AID-CNCR2820640307>3.0.CO;2-I","article-title":"Intake of carotenoids and retinol in relation to risk of prostate cancer","volume":"64","author":"Mettlin","year":"1989","journal-title":"Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Mirahmadi, M., Azimi-Hashemi, S., Saburi, E., Kamali, H., Pishbin, M., and Hadizadeh, F. (2020). Potential inhibitory effect of lycopene on prostate cancer. Biomed. Pharmacother., 129.","DOI":"10.1016\/j.biopha.2020.110459"},{"key":"ref_82","first-page":"861","article-title":"Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy","volume":"10","author":"Kucuk","year":"2001","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/sj.pcan.4500895","article-title":"Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study","volume":"9","author":"Barber","year":"2006","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1177\/153537020222701008","article-title":"Tomato sauce supplementation and prostate cancer: Lycopene accumulation and modulation of biomarkers of carcinogenesis","volume":"227","author":"Bowen","year":"2002","journal-title":"Exp. Biol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1177\/153537020222701007","article-title":"Effects of lycopene supplementation in patients with localized prostate cancer","volume":"227","author":"Kucuk","year":"2002","journal-title":"Exp. Biol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/01635580701413934","article-title":"Lycopene and soy isoflavones in the treatment of prostate cancer","volume":"59","author":"Vaishampayan","year":"2007","journal-title":"Nutr. Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S1078-1439(04)00122-X","article-title":"Lycopene: A novel drug therapy in hormone refractory metastatic prostate cancer","volume":"22","author":"Ansari","year":"2004","journal-title":"Urol. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/nrc3557","article-title":"Serine, glycine and one-carbon units: Cancer metabolism in full circle","volume":"13","author":"Locasale","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Zeng, J.-D., Wu, W.K.K., Wang, H.-Y., and Li, X.-X. (2019). Serine and one-carbon metabolism, a bridge that links mTOR signaling and DNA methylation in cancer. Pharmacol. Res., 149.","DOI":"10.1016\/j.phrs.2019.104352"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1158\/1541-7786.MCR-20-0024","article-title":"Dual Regulation of Histone Methylation by mTOR Complexes Controls Glioblastoma Tumor Cell Growth via EZH2 and SAM","volume":"18","author":"Harachi","year":"2020","journal-title":"Mol. Cancer Res."},{"key":"ref_91","first-page":"845","article-title":"Efficacy of decitabine in malignant meningioma cells: Relation to promoter demethylation of distinct tumor suppressor and oncogenes and independence from TERT","volume":"135","author":"Thomas","year":"2020","journal-title":"J. Neurosurg."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/1978\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:17:52Z","timestamp":1760134672000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/1978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,10]]},"references-count":91,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23041978"],"URL":"https:\/\/doi.org\/10.3390\/ijms23041978","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,10]]}}}