{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:34:31Z","timestamp":1785429271804,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000190","name":"University of Alberta","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000190","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/0160cpw27","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) cytogenetic abnormality and cyclin D1 overexpression. We have found evidence that Forkhead box M1 (FOXM1), a transcription factor with oncogenic potential, is important in the pathogenesis of MCL. Relatively high levels of FOXM1 proteins were detectable in all six MCL cell lines examined. By immunohistochemistry, we consistently found a subset of FOXM1-positive cells in MCL tumors. Analysis of two Gene Expression Omnibus (GEO) datasets from MCL patients showed that elevated FOXM1 levels significantly correlate with a worse clinical outcome. In MCL cell lines, inhibition of FOXM1 using thiostrepton or shRNA effectively triggered apoptosis and significantly reduced cell growth. FOXM1 forms a positive feedback loop with NF\u03baB in MCL cells. Specifically, inhibition of FOXM1 dramatically decreased the protein level\/transcription activity of p65, while enforced FOXM1 expression upregulated p65 and downregulated I\u03baB\u03b1, a key NF\u03baB inhibitor. Conversely, curcumin-mediated NF\u03baB inhibition decreased the protein level\/DNA binding of FOXM1, while transduction of a constitutively active IKK\u03b1 construct into MCL cells significantly dampened the inhibitory effects of thiostrepton. Confocal microscopy revealed that FOXM1 and p65 colocalize with each other. In conclusion, FOXM1 and NF\u03baB work collaboratively in promoting the growth and drug resistance of MCL, and FOXM1 may be a potentially useful therapeutic target.<\/jats:p>","DOI":"10.3390\/cells15090776","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T12:31:56Z","timestamp":1777465916000},"page":"776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FOXM1 and NF\u03baB Form a Positive Feedback Loop to Promote Cell Growth and Drug Resistance in Mantle Cell Lymphoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7417-997X","authenticated-orcid":false,"given":"Yujie","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Basic Medical Science, Nanjing Medical University, Nanjing 211166, China"},{"name":"Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meaad","family":"Almowaled","sequence":"additional","affiliation":[{"name":"College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, Jeddah 22384, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4240-2166","authenticated-orcid":false,"given":"Chuquan","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leizhao","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irwindeep","family":"Sandhu","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada"},{"name":"Department of Oncology, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthea","family":"Peters","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada"},{"name":"Department of Oncology, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada"},{"name":"Department of Oncology, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4000-6372","authenticated-orcid":false,"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada"},{"name":"Department of Oncology, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6963-2407","authenticated-orcid":false,"given":"Raymond","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada"},{"name":"Department of Oncology, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1038\/s41375-023-01962-5","article-title":"Correction: The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"37","author":"Alaggio","year":"2023","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1056\/NEJMoa1306220","article-title":"Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma","volume":"369","author":"Wang","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/hon.3149","article-title":"Mantle cell lymphoma-Update on molecular biology, prognostication and treatment approaches","volume":"41","author":"Silkenstedt","year":"2023","journal-title":"Hematol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"88","DOI":"10.4049\/jimmunol.171.1.88","article-title":"Inhibition of constitutive NF-\u03baB activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis","volume":"171","author":"Pham","year":"2003","journal-title":"J. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13045-018-0621-5","article-title":"NF-kappaB signaling and its relevance to the treatment of mantle cell lymphoma","volume":"11","author":"Balaji","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1158\/1535-7163.MCT-13-0239","article-title":"Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-\u03baB and mTOR Dual-Targeting Approach","volume":"12","author":"Chaturvedi","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1182\/blood-2006-04-015586","article-title":"Constitutive Activation of Akt Contributes to the Pathogenesis and Survival of Mantle Cell Lymphoma","volume":"108","author":"Rudelius","year":"2006","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1002\/cncr.27792","article-title":"Toll-like receptor-4 signaling in mantle cell lymphoma: Effects on tumor growth and immune evasion","volume":"119","author":"Wang","year":"2013","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3406","DOI":"10.1182\/blood-2013-11-538546","article-title":"Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma","volume":"123","author":"Flinn","year":"2014","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wang, J., Zhang, V., Bell, T., Liu, Y., Guo, H., and Zhang, L. (2016, January 2). The Effects of PI3K-\u03b4\/\u03b3 Inhibitor, Duvelisib, in Mantle Cell Lymphoma in Vitro and in Patient-Derived Xenograft Studies. Proceedings of the 58th American Society of Hematology Annual Meeting & Exposition, San Diego, CA, USA. Poster 625.","DOI":"10.1182\/blood.V128.22.3016.3016"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Deshotels, L., Safa, F.M., and Saba, N.S. (2023). NOTCH Signaling in Mantle Cell Lymphoma: Biological and Clinical Implications. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210280"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.semcancer.2017.08.009","article-title":"FoxM1: Repurposing an oncogene as a biomarker","volume":"52","author":"Nandi","year":"2018","journal-title":"Semin. Cancer Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kalathil, D., John, S., and Nair, A.S. (2020). FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.626836"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13058-023-01675-8","article-title":"Targeting the Oncogenic Transcription Factor Foxm1 to Improve Outcomes in All Subtypes of Breast Cancer","volume":"25","author":"Katzenellenbogen","year":"2023","journal-title":"Breast Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.canlet.2013.07.004","article-title":"Foxm1 Promotes the Epithelial to Mesenchymal Transition by Stimulating the Transcription of Slug in Human Breast Cancer","volume":"340","author":"Yang","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6212","DOI":"10.1038\/sj.onc.1210443","article-title":"Aberrant Foxm1b Expression Increases Matrix Metalloproteinase-2 Transcription and Enhances the Invasion of Glioma Cells","volume":"26","author":"Dai","year":"2007","journal-title":"Oncogene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/j.bbagrm.2014.09.016","article-title":"Foxm1: An Emerging Master Regulator of DNA Damage Response and Genotoxic Agent Resistance","volume":"1839","author":"Zona","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Luo, W., Gao, F., Li, S., and Liu, L. (2018). Foxm1 Promotes Cell Proliferation, Invasion, and Stem Cell Properties in Nasopharyngeal Carcinoma. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00483"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.bbagrm.2011.09.004","article-title":"FOXM1: From cancer initiation to progression and treatment","volume":"1819","author":"Koo","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6471","DOI":"10.1038\/ncomms7471","article-title":"Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia","volume":"6","author":"Buchner","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.leukres.2014.12.005","article-title":"Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line","volume":"39","author":"Tufekci","year":"2015","journal-title":"Leuk. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.3892\/mmr.2015.3469","article-title":"Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia","volume":"12","author":"Wang","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/leu.2015.334","article-title":"FOXM1 is a therapeutic target for high-risk multiple myeloma","volume":"30","author":"Gu","year":"2016","journal-title":"Leukemia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.3324\/haematol.2011.053421","article-title":"Overexpression of FoxM1 offers a promising therapeutic target in diffuse large B-cell lymphoma","volume":"97","author":"Uddin","year":"2012","journal-title":"Haematologica"},{"key":"ref_25","first-page":"300","article-title":"Validation of FOXM1 as a therapeutic target in acute myeloid leukemia","volume":"130","author":"Khan","year":"2017","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Haque, M., Li, J., Huang, Y.-H., Almowaled, M., Barger, C.J., Karpf, A.R., Wang, P., Chen, W., Turner, S.D., and Lai, R. (2019). NPM-ALK is a key regulator of the oncoprotein FOXM1 in ALK-positive anaplastic large cell lymphoma. Cancers, 11.","DOI":"10.3390\/cancers11081119"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4176","DOI":"10.1182\/blood-2018-99-119349","article-title":"FoxM1-Mediated Signaling Promotes the Progression of Mantle Cell Lymphoma","volume":"132","author":"Guo","year":"2018","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"424","DOI":"10.5858\/2003-127-0424-COMCLC","article-title":"Characterization of 4 mantle cell lymphoma cell lines","volume":"127","author":"Amin","year":"2003","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5171","DOI":"10.1182\/blood-2008-02-139212","article-title":"Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma","volume":"112","author":"Gelebart","year":"2008","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Shang, C., Lai, J., Haque, M., Chen, W., Wang, P., and Lai, R. (2023). Nuclear NPM-ALK protects Myc from proteasomal degradation and contributes to its high expression in cancer stem-like cells in ALK-positive anaplastic large cell lymphoma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241814337"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Liu, C., Barger, C.J., and Karpf, A.R. (2021). FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer. Cancers, 13.","DOI":"10.3390\/cancers13123065"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Blenk, S., Engelmann, J.C., Pinkert, S., Weniger, M., Schultz, J., Rosenwald, A., Muller-Hermelink, H.K., Muller, T., and Dandekar, T. (2008). Explorative data analysis of MCL reveals gene expression networks implicated in survival and prognosis supported by explorative CGH analysis. BMC Cancer, 8.","DOI":"10.1186\/1471-2407-8-106"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1200\/JCO.2016.70.7901","article-title":"New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies","volume":"35","author":"Scott","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hoster, E., Klapper, W., Rosenwald, A., Bernd, H.-W., Hartmann, S., Loddenkemper, C., Barth, T.F., Hiddemann, W., Unterhalt, M., and Kluin-Nelemans, H.C. (2012, January 16). Cell Proliferation (Ki-67) as Prognostic Marker in Mantle Cell Lymphoma. Proceedings of the American Society of Hematology Annual Meeting, Atlanta, GA, USA. Poster 622.","DOI":"10.1182\/blood.V120.21.2677.2677"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1182\/blood-2015-11-681460","article-title":"Pathogenic role of B-cell receptor signaling and canonical NF-kappaB activation in mantle cell lymphoma","volume":"128","author":"Saba","year":"2016","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/embr.201337983","article-title":"The IkappaB kinase complex in NF-kappaB regulation and beyond","volume":"15","author":"Hinz","year":"2014","journal-title":"EMBO Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4919","DOI":"10.4049\/jimmunol.167.9.4919","article-title":"Phosphorylation by the protein kinase CK2 promotes calpain-mediated degradation of IkappaBalpha","volume":"167","author":"Shen","year":"2001","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.bcp.2005.04.043","article-title":"Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1\/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma","volume":"70","author":"Shishodia","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1158\/1078-0432.CCR-16-0226","article-title":"Anthelmintic Niclosamide Disrupts the Interplay of p65 and FOXM1\/beta-catenin and Eradicates Leukemia Stem Cells in Chronic Myelogenous Leukemia","volume":"23","author":"Jin","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1177\/0960327120984225","article-title":"FOXM1 regulates the proliferation, apoptosis and inflammatory response of keratinocytes through the NF-\u03baB signaling pathway","volume":"40","author":"Zhou","year":"2021","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/j.celrep.2014.07.037","article-title":"The NF-kappaB genomic landscape in lymphoblastoid B cells","volume":"8","author":"Zhao","year":"2014","journal-title":"Cell Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1182\/blood.2022015560","article-title":"Ibrutinib improves survival compared with chemotherapy in mantle cell lymphoma with central nervous system relapse","volume":"140","author":"Rusconi","year":"2022","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1182\/blood-2014-10-603738","article-title":"STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma","volume":"126","author":"Wu","year":"2015","journal-title":"Blood"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/9\/776\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T04:14:50Z","timestamp":1777522490000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/9\/776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,25]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cells15090776"],"URL":"https:\/\/doi.org\/10.3390\/cells15090776","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,25]]}}}