The Proinflammatory Secretome of Senescent Cells Can Be Controlled by a HIF2A ‐Dependent Upregulation and a FURIN ‐Dependent Cleavage of the ANGPTL4 Secreted Factor
Year: 2025
Type: article
Abstract: Senescent cells are characterized by a stable proliferation arrest and a senescence-associated secretory phenotype or SASP. Although these cells can have some beneficial effects, including protecting from tumor formation, their accumulation is deleterious during aging as it promotes age-related diseases, including cancer initiation and progression. Although the SASP has a critical role, its composition, regulation and dual role in cancer remain largely misunderstood. Here, we show that ANGPTL4 is one of the rare secreted factors induced in many different types of senescent cells. Importantly, ANGPTL4 knockdown during senescence or its constitutive expression, respectively inhibits or induces classical proinflammatory SASP factors, such as IL1A, IL6 and IL8. The latter effect is mediated upstream of IL1A, an early SASP factor, suggesting an upstream role of ANGPTL4 in SASP induction. This ANGPTL4-dependent proinflammatory SASP can promote human neutrophil activation in ex vivo assays, or tumor initiation in a KRAS-dependent lung tumorigenesis model in mice. This upstream activity of ANGPTL4 in regulating the proinflammatory SASP depends on its upregulation following a hypoxia-like response and HIF2A activation, and its proteolytic processing by the FURIN proprotein convertase. Altogether these findings shed light on a two-step activation of ANGPTL4 by HIF2A and FURIN in senescent cells and its upstream role in promoting the proinflammatory SASP, cancer and potentially other senescence-associated diseases.
Source: Aging Cell
DOI: 10.1111/acel.70307
Authors: Gabriela Makulyte, Hasan Safwan‐Zaiter, Delphine Goehrig, Anda Huna, Adèle Mangelinck, Takumi Mikawa, Alberta Palazzo, Lyvia Moudombi, Jean‐Jacques Medard, Marie Chanal, Pacôme Lecot, Marie‐Cécile Michallet, Julie Gavard, Serge Adnot, Pierre Dubus, Hiroshi Kondoh, Carl Mann, Nguan Soon Tan, Philippe Bertolino, Jean‐Michel Flaman, David Bernard
Institutions: Centre National de la Recherche Scientifique, Inserm, La Ligue Contre le Cancer, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, CEA Paris-Saclay - Etablissement de Saclay, Institut de Biologie Intégrative de la Cellule, Kyoto University, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, Institut de Cancérologie de l'Ouest, Université d'Angers, Nantes Université, Justus-Liebig-Universität Gießen, Centre Hospitalier Universitaire Henri-Mondor, Hôpitaux Universitaires Henri-Mondor, Université de Bordeaux, Centre Hospitalier Universitaire de Bordeaux, BoRdeaux Institute of onCology, Nanyang Technological University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
OpenAlex ID: W4417043586