Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells

Francesco Prattichizzo, Angelica Giuliani, Rina Recchioni, Massimiliano Bonafè, Fiorella Marcheselli, Sabrina De Carolis, A. Campanati, Katia Giuliodori, M. R. Rippo, Francesca Brugè, Luca Tiano, Carla Micucci, Antonio Ceriello, A. Offidani, Antonio Procopio, Fabiola Olivieri

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)11945-11958
Number of pages14
JournalOncotarget
Volume7
Issue number11
DOIs
Publication statusPublished - Mar 15 2016

Keywords

  • Gerotarget
  • HUVEC
  • miR-126-3p
  • miR-146α-5p
  • Replicative senescence
  • SASP

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells'. Together they form a unique fingerprint.

Cite this