Research Papers: Gerotarget (Focus on Aging):
Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells
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Francesco Prattichizzo1,2, Angelica Giuliani1, Rina Recchioni3, Massimiliano Bonafè4, Fiorella Marcheselli3, Sabrina De Carolis4, Anna Campanati5, Katia Giuliodori5, Maria Rita Rippo1, Francesca Brugè6, Luca Tiano6, Carla Micucci1, Antonio Ceriello2, Annamaria Offidani5, Antonio Domenico Procopio1,3 and Fabiola Olivieri1,3
1 Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy
2 Insititut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain and IRCCS MultiMedica Sesto San Giovanni (MI), Italy
3 Center of Clinical Pathology and Innovative Therapy, National Institute INRCA-IRCCS, Ancona, Italy
4 Department of Experimental, Diagnostic and Specialty Medicine, DIMES, University of Bologna, Bologna, Italy
5 Dermatology Clinic, Department of Clinical and Molecular Medicine, Università Politecnica delle Marche, Ancona, Italy
6 Department of Clinical and Dental Sciences, DISCO, Università Politecnica delle Marche, Ancona, Italy
Anna Campanati, email:
Keywords: miR-146a-5p, miR-126-3p, SASP, HUVEC, replicative senescence, Gerotarget
Received: December 04, 2015 Accepted: February 14, 2016 Published: March 02, 2016
Endothelial cell senescence is characterized by acquisition of senescence-associated secretory phenotype (SASP), able to promote inflammaging and cancer progression. Emerging evidence suggest that preventing SASP development could help to slow the rate of aging and the progression of age-related diseases, including cancer. Aim of this study was to evaluate whether and how adalimumab, a monoclonal antibody directed against tumor necrosis factor-α (TNF-α), a major SASP component, can prevent the SASP. A three-pronged approach has been adopted to assess the if adalimumab is able to: i) modulate a panel of classic and novel senescence- and SASP-associated markers (interleukin [IL]-6, senescence associated-β-galactosidase, p16/Ink4a, plasminogen activator inhibitor 1, endothelial nitric oxide synthase, miR-146a-5p/Irak1 and miR-126-3p/Spred1) in human umbilical vein endothelial cells (HUVECs); ii) reduce the paracrine effects of senescent HUVECs’ secretome on MCF-7 breast cancer cells, through wound healing and mammosphere assay; and iii) exert significant decrease of miR-146a-5p and increase of miR-126-3p in circulating angiogenic cells (CACs) from psoriasis patients receiving adalimumab in monotherapy.
TNF-α blockade associated with adalimumab induced significant reduction in released IL-6 and significant increase in eNOS and miR-126-3p expression levels in long-term HUVEC cultures.
A significant reduction in miR-146a-5p expression levels both in long-term HUVEC cultures and in CACs isolated from psoriasis patients was also evident. Interestingly, conditioned medium from senescent HUVECs treated with adalimumab was less consistent than medium from untreated cells in inducing migration- and mammosphere- promoting effects on MCF-7 cells.
Our findings suggest that adalimumab can induce epigenetic modifications in cells undergoing senescence, thus contributing to the attenuation of SASP tumor-promoting effects.
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