The Proinflammatory Secretome of Senescent Cells Can Be Controlled by a <scp>HIF2A</scp> ‐Dependent Upregulation and a <scp>FURIN</scp> ‐Dependent Cleavage of the <scp>ANGPTL4</scp> Secreted Factor
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.
Authors
- Takumi Mikawa (ORCID: https://orcid.org/0009-0008-7352-4282)
- Marie Chanal (ORCID: https://orcid.org/0000-0001-8069-8821)
- Serge Adnot (ORCID: https://orcid.org/0000-0001-5666-3063)
- Pierre Dubus (ORCID: https://orcid.org/0000-0003-1803-4711)
- Hasan Safwan‐Zaiter
- Philippe Bertolino (ORCID: https://orcid.org/0000-0001-8064-8269)
- Alberta Palazzo
- Jean‐Jacques Médard
- David Bernard (ORCID: https://orcid.org/0000-0002-1557-2074)
- Jean‐Michel Flaman (ORCID: https://orcid.org/0000-0003-3544-0199)
- Carl Mann (ORCID: https://orcid.org/0000-0001-7212-1512)
- Lyvia Moudombi
- Julie Gavard (ORCID: https://orcid.org/0000-0002-7985-9007)
- Nguan Soon Tan (ORCID: https://orcid.org/0000-0003-0136-7341)
- Adèle Mangelinck (ORCID: https://orcid.org/0009-0008-7454-8198)
- Anda Huna (ORCID: https://orcid.org/0000-0003-2030-8865)
- Marie‐Cécile Michallet (ORCID: https://orcid.org/0000-0001-5860-7460)
- Pacôme Lecot (ORCID: https://orcid.org/0000-0001-6338-8784)
- Hiroshi Kondoh (ORCID: https://orcid.org/0000-0002-1067-2244)
- Gabriela Makulyte
- Delphine Goehrig
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Inserm (FR)
- Nanyang Technological University (SG)
- Université Paris-Est Créteil (FR)
- Justus-Liebig-Universität Gießen (DE)
- Kyoto University (JP)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR)
- La Ligue Contre le Cancer (FR)
- Institut de Cancérologie de l'Ouest (FR)
- Bordeaux Population Health (FR)
- Institut de Biologie Intégrative de la Cellule (FR)
- Institut Génétique Nantes Atlantique (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- CEA Paris-Saclay (FR)
- Hôpitaux Universitaires Henri-Mondor (FR)
- BoRdeaux Institute of onCology (FR)
- Nantes Université (FR)
Publication Details
- Journal
- Aging Cell
- Published
- 2025-12-05
- DOI
- https://doi.org/10.1111/acel.70307
- Primary Topic
- Lipid metabolism and disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Institut National Du Cancer