{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:54:28Z","timestamp":1791557668107,"version":"4.3.4"},"reference-count":41,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T00:00:00Z","timestamp":1643068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003329","name":"Ministry of Economy, Industry and Competitiveness","doi-asserted-by":"publisher","award":["SAF-2017-83351R"],"award-info":[{"award-number":["SAF-2017-83351R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Centre for Biomedical Network Research on Rare Diseases","award":["U-707"],"award-info":[{"award-number":["U-707"]}]},{"name":"Proyecto Intramural Especial CSIC","award":["PIE-201820E073"],"award-info":[{"award-number":["PIE-201820E073"]}]},{"name":"Alianza Espa\u00f1ola de pacientes y familiares de von Hippel Lindau AVHL","award":["lab 109"],"award-info":[{"award-number":["lab 109"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Von Hippel-Lindau (VHL) syndrome is a rare inherited cancer disease where the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HBs), CNS-HBs, and clear cell renal cell carcinoma (ccRCC). Since standard therapies in VHL have shown limited response, leaving surgery as the only possible treatment, targeting of the \u03b22-adrenergic receptor (ADRB2) has shown therapeutic antitumor benefits on VHL-retinal HBs (clinical trial), VHL-CNS HBs, and VHL-ccRCC (in vitro and in vivo). In the present study, we wanted to look deep into the effects of the ADRB2 blockers propranolol and ICI-118,551 on two main aspects of cancer progression: (i) the changes on the inflammatory response of ccRCC cells; and (ii) the modulation on the Warburg effect (glycolytic metabolism), concretely, on the expression of genes involved in the cell reactive oxygen species (ROS) balance and levels. Accordingly, in vitro studies with primary VHL-ccRCC and 786-O cells measuring ROS levels, ROS-expression of detoxifying enzymes, and the expression of p65\/NF-\u03baB targets by RT-PCR were carried out. Furthermore, histological analyses of ccRCC samples from heterotopic mouse xenografts were performed. The obtained results show that ADRB2 blockade in ccRCC cells reduces the level of oxidative stress and stabilizes the inflammatory response. Thus, these data further support the idea of targeting ADRB2 as a promising strategy for the treatment of VHL and other non-VHL tumors.<\/jats:p>","DOI":"10.3390\/ijms23031325","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T20:38:58Z","timestamp":1643143138000},"page":"1325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Blockade of \u03b22-Adrenergic Receptor Reduces Inflammation and Oxidative Stress in Clear Cell Renal Cell Carcinoma"],"prefix":"10.3390","volume":"23","author":[{"given":"Virginia","family":"Albi\u00f1ana","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margaritas Salas, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Recio-Poveda","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margaritas Salas, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Gonz\u00e1lez-Peramato","sequence":"additional","affiliation":[{"name":"Department of Pathology, La Paz University Hospital, Autonomous University of Madrid, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Martinez-Pi\u00f1eiro","sequence":"additional","affiliation":[{"name":"Department of Urology, Instituto de Investigaci\u00f3n IdiPaz, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6310-2245","authenticated-orcid":false,"given":"Luisa Mar\u00eda","family":"Botella","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margaritas Salas, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6596-9600","authenticated-orcid":false,"given":"Angel M.","family":"Cuesta","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1038\/s41467-017-01965-8","article-title":"HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism","volume":"8","author":"Du","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Albi\u00f1ana, V., Gallardo-Vara, E., de Rojas-P, I., Recio-Poveda, L., Aguado, T., Canto-Cano, A., Aguirre, D.T., Serra, M.M., Gonz\u00e1lez-Peramato, P., and Mart\u00ednez-Pi\u00f1eiro, L. (2020). Targeting \u03b22-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel\u2013Lindau Disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9092740"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.1038\/sj.onc.1203938","article-title":"Up-regulation of hypoxia-inducible factors HIF-1\u03b1 and HIF-2\u03b1 under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function","volume":"19","author":"Krieg","year":"2000","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/j.jocn.2013.10.023","article-title":"Hemangioblastomas in the elderly: Epidemiology and clinical characteristics","volume":"21","author":"Kassardjian","year":"2014","journal-title":"J. Clin. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/S0022-5347(01)62509-6","article-title":"Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma","volume":"160","author":"Neumann","year":"1998","journal-title":"J. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nrneph.2013.144","article-title":"Renal cancer in von Hippel-Lindau disease and related syndromes","volume":"9","author":"Bausch","year":"2013","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1097\/PAS.0b013e3181ddf54d","article-title":"VHL-gene deletion in single renal tubular epithelial cells and renal tubular cysts: Further evidence for a cyst-dependent progression pathway of clear cell renal carcinoma in von hippel-lindau disease","volume":"34","author":"Montani","year":"2010","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"490","DOI":"10.3389\/fonc.2019.00490","article-title":"Targeting the tumor microenvironment in renal cell cancer biology and therapy","volume":"9","author":"Heidegger","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5003","DOI":"10.1200\/JCO.2020.38.15_suppl.5003","article-title":"Phase II study of the oral HIF-2\u03b1 inhibitor MK-6482 for Von Hippel-Lindau disease\u2013associated renal cell carcinoma","volume":"38","author":"Jonasch","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/s41591-021-01324-7","article-title":"Inhibition of hypoxia-inducible factor-2\u03b1 in renal cell carcinoma with belzutifan: A phase 1 trial and biomarker analysis","volume":"27","author":"Choueiri","year":"2021","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.1056\/NEJMc0708819","article-title":"Propranolol for severe hemangiomas of infancy","volume":"358","author":"Hubiche","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s13023-015-0343-5","article-title":"Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients","volume":"10","author":"Segura","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13023-017-0664-7","article-title":"Repurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease","volume":"12","author":"Escribano","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10062","DOI":"10.1038\/s41598-019-46448-6","article-title":"The \u03b22-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease","volume":"9","author":"Cuesta","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1002\/jcp.29969","article-title":"The tumour microenvironment and metabolism in renal cell carcinoma targeted or immune therapy","volume":"236","author":"Lai","year":"2021","journal-title":"J. Cell Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"de Rojas-P, I., Albi\u00f1ana, V., Taranets, L., Recio-Poveda, L., Cuesta, A.M., Popov, N., Kronenberger, T., and Botella, L.M. (2021). The Endothelial Landscape and Its Role in Von Hippel\u2013Lindau Disease. Cells, 10.","DOI":"10.3390\/cells10092313"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"g4797","DOI":"10.1136\/bmj.g4797","article-title":"Renal cell carcinoma","volume":"349","author":"Jonasch","year":"2014","journal-title":"BMJ"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1126\/science.8493574","article-title":"Identification of the von Hippel-Lindau disease tumor suppressor gene","volume":"260","author":"Latif","year":"1993","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1016\/S0140-6736(03)13643-4","article-title":"Von Hippel-Lindau disease","volume":"361","author":"Lonser","year":"2003","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.6004\/jnccn.2014.0129","article-title":"Genetic kidney cancer syndromes","volume":"12","author":"Ho","year":"2014","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4726","DOI":"10.1158\/1078-0432.CCR-07-4921","article-title":"Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors","volume":"14","author":"Nickerson","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1016\/j.febslet.2012.04.032","article-title":"Systemic VHL gene functions and the VHL disease","volume":"586","author":"Bader","year":"2012","journal-title":"FEBS Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/20459","article-title":"The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis","volume":"399","author":"Maxwell","year":"1999","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc3183","article-title":"HIF1alpha and HIF2alpha: Sibling rivalry in hypoxic tumour growth and progression","volume":"12","author":"Keith","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.eururo.2015.08.007","article-title":"Hypoxia, hypoxia-inducible transcription factors, and renal cancer","volume":"69","author":"Grampp","year":"2016","journal-title":"Eur. Urol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5605","DOI":"10.1158\/1078-0432.CCR-15-1673","article-title":"Tyrosine kinase signaling in clear cell and papillary renal cell carcinoma revealed by mass spectrometry-based phosphotyrosine proteomics","volume":"22","author":"Haake","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12935-018-0530-2","article-title":"Crosstalk between VEGFR and other receptor tyrosine kinases for TKI therapy of metastatic renal cell carcinoma","volume":"18","author":"Lai","year":"2018","journal-title":"Cancer Cell Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nature19796","article-title":"Targeting renal cell carcinoma with a HIF-2 antagonist","volume":"539","author":"Chen","year":"2016","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.cell.2019.12.026","article-title":"Clinical Proteomic Tumor Analysis Consortium. Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma","volume":"180","author":"Clark","year":"2020","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.cmet.2018.07.020","article-title":"Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo","volume":"28","author":"Courtney","year":"2018","journal-title":"Cell Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.semnephrol.2018.01.006","article-title":"Metabolomics and Metabolic Reprogramming in Kidney Cancer","volume":"38","author":"Weiss","year":"2018","journal-title":"Semin. Nephrol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nrd3137","article-title":"Targeting mitochondria for cancer therapy","volume":"9","author":"Fulda","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1007\/s12272-019-01185-2","article-title":"Warburg effect and its role in tumourigenesis","volume":"42","author":"Lebelo","year":"2019","journal-title":"Arch. Pharmacal Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/his.13735","article-title":"Grading of renal cell carcinoma","volume":"74","author":"Delahunt","year":"2019","journal-title":"Histopathology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/0005-2760(82)90150-3","article-title":"Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides","volume":"710","author":"Ursini","year":"1982","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1038\/ncb3064","article-title":"Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice","volume":"16","author":"Schneider","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7546","DOI":"10.1128\/MCB.25.17.7546-7556.2005","article-title":"Mechanism of von Hippel-Lindau Protein-Mediated Suppression of Nuclear Factor kappa B Activity","volume":"25","author":"An","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.molcel.2007.09.010","article-title":"pVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-\u03baB Agonist Card9 by CK2","volume":"28","author":"Yang","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Peri, S., Devarajan, K., Yang, D.H., Knudson, A.G., and Balachandran, S. (2013). Meta-Analysis Identifies NF-\u03baB as a Therapeutic Target in Renal Cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076746"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1325\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:07:04Z","timestamp":1760134024000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,25]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031325"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031325","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,25]]}}}