{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T06:08:01Z","timestamp":1777529281686,"version":"3.51.4"},"reference-count":55,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,9]],"date-time":"2021-01-09T00:00:00Z","timestamp":1610150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Forschungsf\u00f6rderung  of the Charit\u00e9","award":["514611801"],"award-info":[{"award-number":["514611801"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human cytomegalovirus (HCMV) has been implicated in the development of human malignancies, for instance in colon cancer. Proteasome inhibitors were developed for cancer therapy and have also been shown to influence HCMV infection. The aim of this study was to investigate if proteasome inhibitors have therapeutic potential for colon carcinoma and how this is influenced by HCMV infection. We show by immunofluorescence and flow cytometry that the colon carcinoma cell line Caco-2 is susceptible to HCMV infection. Growth curve analysis as well as protein expression kinetics and quantitative genome analysis further confirm these results. HCMV has an anti-apoptotic effect on Caco-2 cells by inhibiting very early events of the apoptosis cascade. Further investigations showed that HCMV stabilizes the membrane potential of the mitochondria, which is typically lost very early during apoptosis. This stabilization is resistant to proteasome inhibitor Bortezomib treatment, allowing HCMV-infected cells to survive apoptotic signals. Our findings indicate a possible role of proteasome inhibitors in colon carcinoma therapy.<\/jats:p>","DOI":"10.3390\/v13010083","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T23:03:42Z","timestamp":1610319822000},"page":"83","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["HCMV-Mediated Interference of Bortezomib-Induced Apoptosis in Colon Carcinoma Cell Line Caco-2"],"prefix":"10.3390","volume":"13","author":[{"given":"Heike","family":"H\u00e4rtel","sequence":"first","affiliation":[{"name":"Institute of Virology, Charit\u00e9-Universit\u00e4tsmedizin-Berlin, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine","family":"Thei\u00df","sequence":"additional","affiliation":[{"name":"Institute of Virology, Charit\u00e9-Universit\u00e4tsmedizin-Berlin, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed O.","family":"Abdelaziz","sequence":"additional","affiliation":[{"name":"Institute of Virology, Charit\u00e9-Universit\u00e4tsmedizin-Berlin, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin J.","family":"Raftery","sequence":"additional","affiliation":[{"name":"Medical Clinic of Hematology, Oncology and Tumorimmunology, CCM, Charit\u00e9-Universit\u00e4tsmedizin-Berlin, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Pecher","sequence":"additional","affiliation":[{"name":"Medical Clinic of Hematology, Oncology and Tumorimmunology, CCM, Charit\u00e9-Universit\u00e4tsmedizin-Berlin, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7622-2900","authenticated-orcid":false,"given":"Elke","family":"Bogner","sequence":"additional","affiliation":[{"name":"Institute of Virology, Charit\u00e9-Universit\u00e4tsmedizin-Berlin, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,9]]},"reference":[{"key":"ref_1","unstructured":"Fields, B.N., Knipe, D.M., and Howley, P.M. (1996). Cytomegalovirus. Fields Virology, Raven Press. [3rd ed.]."},{"key":"ref_2","first-page":"1960","article-title":"Cytomegalovirus","volume":"Volume 2","author":"Knipe","year":"2013","journal-title":"Fields Virology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1007\/s00705-012-1299-6","article-title":"Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses","volume":"157","author":"Adams","year":"2012","journal-title":"Arch. Virol."},{"key":"ref_4","first-page":"3347","article-title":"Human cytomegalovirus infection and expression in human malignant glioma","volume":"62","author":"Cobbs","year":"2002","journal-title":"Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1016\/S0140-6736(02)11524-8","article-title":"Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer","volume":"360","author":"Harkins","year":"2002","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1215\/15228517-2007-035","article-title":"Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma","volume":"10","author":"Mitchell","year":"2008","journal-title":"Neuro. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1097\/01.ju.0000080263.46164.97","article-title":"High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma","volume":"170","author":"Samanta","year":"2003","journal-title":"J. Urol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.tranon.2014.09.008","article-title":"High prevalence of human cytomegalovirus in brain metastases of patients with primary breast and colorectal cancers","volume":"7","author":"Taher","year":"2014","journal-title":"Transl. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.jcv.2012.04.007","article-title":"Human cytomegalovirus preferentially infects the neoplastic epithelium of colorectal cancer: A quantitative and histological analysis","volume":"54","author":"Chen","year":"2012","journal-title":"J. Clin. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1053\/bega.2001.0280","article-title":"Epidemiology and screening of colorectral cancer","volume":"16","author":"Faivre","year":"2002","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1111\/1469-0691.12412","article-title":"Tumoral presence of human cytomegalovirus is associated with shorter disease-free survival in elderly patients with colorectal cancer and higher levels of intratumoral interleukin-17","volume":"20","author":"Chen","year":"2014","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1099\/jgv.0.000558","article-title":"Identification of human cytomegalovirus in tumour tissues of colorectal cancer and its association with the outcome of non-elderly patients","volume":"97","author":"Chen","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1099\/jgv.0.000315","article-title":"Serological and viraemic status of human cytomegalovirus infection in patients with colorectal cancer is not correlated with viral replication and transcription in tumours","volume":"91","author":"Chen","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.femsre.2003.07.005","article-title":"Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: A novel role for viral infection in tumor progression","volume":"28","author":"Cinatl","year":"2004","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1128\/JVI.72.5.3729-3741.1998","article-title":"Cell cycle dysregulation by human cytomegalovirus: Influence of the cell cycle phase at the time of infection and effects on cyclin transcription","volume":"72","author":"Salvant","year":"1998","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1007\/s00018-004-3417-4","article-title":"Cytomegalovirus infection blocks apoptosis in cancer cells","volume":"61","author":"Michaelis","year":"2004","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1124\/mol.118.112797","article-title":"Bortezomib targets Sp transcription factors in cancer cells","volume":"94","author":"Karki","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_18","first-page":"76","article-title":"Bortezomib induces G2-M arrest in human colon cancer cells through ROS-inducible phosphorylation of ATM-CHK1","volume":"41","author":"Hong","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e01180-18","DOI":"10.1128\/JVI.01180-18","article-title":"The abundant tegument protein pUL25 of human cytomegalovirus prevents proteasomal degradation of pUL26 and supports its suppression of ISGylation","volume":"92","author":"Zimmermann","year":"2018","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e01774-17","DOI":"10.1128\/JVI.01774-17","article-title":"Human cytomegalovirus tegument protein pp65 (pUL83) dampens type I interferon production by inactivating the DNA sensor cGAS without affecting STING","volume":"92","author":"Biolatti","year":"2018","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.3389\/fmicb.2017.01854","article-title":"Human cytomegalovirus IE2 86 kDa protein induces STING degradation and inhibits cGAMP-mediated IFN-\u03b2 induction","volume":"26","author":"Kim","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9575","DOI":"10.1073\/pnas.1207496109","article-title":"BclAF1 restriction factor is neutralized by proteasomal degradation and microRNA repression during human cytomegalovirus infection","volume":"109","author":"Lee","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/sj.onc.1210744","article-title":"BCL-2 family regulation by the 20S proteasome inhibitor bortezomib","volume":"27","author":"Fennell","year":"2008","journal-title":"Oncogene"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7988","DOI":"10.1073\/pnas.0401897101","article-title":"Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria","volume":"101","author":"Arnoult","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Brune, W., and Andoniou, C.E. (2017). Die another day: Inhibition of cell death pathways by cytomegalovirus. Viruses, 9.","DOI":"10.3390\/v9090249"},{"key":"ref_26","first-page":"201914667","article-title":"Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells","volume":"22","author":"Chaudhry","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3109","DOI":"10.1128\/JVI.02124-06","article-title":"Human cytomegalovirus UL38 protein blocks apoptosis","volume":"81","author":"Terhune","year":"2007","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1111\/j.1582-4934.2007.00032.x","article-title":"Pathogenesis of colorectal carcinoma and therapeutic implications: The roles of the ubiquitin-proteasome system and Cox-2","volume":"11","author":"Voutsadakis","year":"2007","journal-title":"J. Cell. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1475-2867-5-18","article-title":"Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy","volume":"5","author":"Boccadoro","year":"2005","journal-title":"Cancer Cell Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3458","DOI":"10.1158\/0008-5472.CAN-17-2296","article-title":"PSMD5 inactivation promotes 26S proteasome assembly during colorectal tumor progression","volume":"78","author":"Levin","year":"2018","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/sj.leu.2404528","article-title":"Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphomas","volume":"21","author":"Bonvini","year":"2007","journal-title":"Leukemia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1007\/s00280-014-2463-3","article-title":"Effects of a novel proteasome inhibitor BU-32 on multiple myeloma cells","volume":"73","author":"Roy","year":"2014","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S1535-6108(04)00120-5","article-title":"The development of proteasome inhibitors as anticancer drugs","volume":"5","author":"Adams","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1128\/JVI.79.5.2754-2767.2005","article-title":"Human cytomegalovirus labeled with green fluorescent protein for live analysis of intracellular Particle Movements","volume":"79","author":"Sampaio","year":"2005","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1099\/0022-1317-78-8-1981","article-title":"The human cytomegalovirus glycoprotein B gene (ORF UL55) is expressed early in the infectious cycle","volume":"78","author":"Smuda","year":"1997","journal-title":"J. Gen. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1023\/A:1018906504944","article-title":"Regulation of tight junction permeability by calcium mediators and cell cytoskeleton in rabbit tracheal epithelium","volume":"10","author":"Bhat","year":"1993","journal-title":"Pharm. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.bbamem.2008.09.016","article-title":"Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery","volume":"1788","author":"Deli","year":"2008","journal-title":"Biochim. Biohys. Acta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1128\/AAC.31.4.544","article-title":"Pyrrolo[2,3-d]pyrimidine nucleosides as inhibitors of human cytomegalovirus","volume":"31","author":"Turk","year":"1987","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5769","DOI":"10.1128\/JVI.76.11.5769-5783.2002","article-title":"Functional interaction between the pp71 protein of human cytomegalovirus and the PML-interacting protein human Daxx","volume":"76","author":"Hofmann","year":"2002","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4552","DOI":"10.1128\/JVI.73.6.4552-4560.1999","article-title":"Human cytomegalovirus infection of Caco-2 cells occurs at the basolateral membrane and is differentiation state dependent","volume":"73","author":"Jarvis","year":"1999","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1128\/JVI.74.1.513-517.2000","article-title":"Human cytomegalovirus infects Caco-2 intestinal epithelial cells basolaterally regardless of the differentiation state","volume":"74","author":"Esclatine","year":"2000","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1128\/JVI.80.2.710-722.2006","article-title":"Human cytomegalovirus entry into epithelial and endothelial cells depends on genes UL128 to UL150 and occurs by endocytosis and low-pH fusion","volume":"80","author":"Ryckman","year":"2006","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41419-017-0081-9","article-title":"Epstein-Barr virus encoded latent membrane protein 1 suppresses necroptosis through targeting RIPK1\/3 ubiquitination","volume":"9","author":"Liu","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"20901","DOI":"10.1073\/pnas.1217094110","article-title":"Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA","volume":"109","author":"Ma","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"31373","DOI":"10.1038\/srep31373","article-title":"The cytomegalovirus protein pUL37x1 targets mitochondria to mediate neuroprotection","volume":"6","author":"Hong","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.chom.2015.01.003","article-title":"Herpes simplex virus suppresses necroptosis in human cells","volume":"17","author":"Guo","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11635","DOI":"10.1074\/jbc.M115.646042","article-title":"Suppression of RIP3-dependent necroptosis by human cytomegalovirus","volume":"290","author":"Omoto","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/tid.12162","article-title":"High incidence of post-transplant cytomegalovirus reactivations in myeloma patients undergoing autologous stem cell transplantation after treatment with bortezomib-based regimens: A survey from the Rome transplant network","volume":"16","author":"Marchesi","year":"2014","journal-title":"Transpl. Infect. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1016\/j.transproceed.2017.05.007","article-title":"Is cytomegalovirus surveillance necessary for patients with low reactivation risk in an autologous hematopoietic cell transplantation setting?","volume":"49","author":"Kaya","year":"2017","journal-title":"Transpl. Proc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/ejh.13366","article-title":"Cytomegalovirus reactivation after bortezomib treatment for multiple myeloma and light chain amyloidosis","volume":"104","author":"Sharpley","year":"2020","journal-title":"Eur. J. Haematol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s12013-014-0224-x","article-title":"Drug-induced modulation of T lymphocytes as a potential mechanism of susceptibility to infections in patients with multiple myeloma during bortezomib therapy","volume":"71","author":"Li","year":"2015","journal-title":"Cell Biochem. Biophys."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/path.5224","article-title":"Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma","volume":"248","author":"Neuzillet","year":"2019","journal-title":"J. Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1158\/0008-5472.CAN-07-5714","article-title":"Cancer-associated stromal fibroblasts promote pancreatic tumor progression","volume":"68","author":"Hwang","year":"2008","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Cavaco, A.C.M., Rezaei, M., Caliandro, M.F., Lima, A.M., Stehling, M., Dhayat, A., Haier, J., Brakebusch, C., and Eble, J.A. (2018). The interaction between laminin-332 and alpha3beta1 integrin determines differentiation and maintenance of CAFs, and supports invasion of pancreatic duct adenocarcinoma cells. Cancers, 11.","DOI":"10.3390\/cancers11010014"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.molmed.2013.05.004","article-title":"\u2018Cancer associated fibroblasts\u2019\u2014More than meets the eye","volume":"19","author":"Madar","year":"2013","journal-title":"Trends Mol. Med."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/1\/83\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:09:06Z","timestamp":1760159346000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/1\/83"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,9]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["v13010083"],"URL":"https:\/\/doi.org\/10.3390\/v13010083","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,9]]}}}