Research Paper Volume 16, Issue 21 pp 13201—13224
Prostaglandin E2 regulates senescence and post-senescence neoplastic escape in primary human keratinocytes
- 1 CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 – U1277 – CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille F-59000, France
- 2 Direction of Clinical Research and Innovation, Oscar Lambret Center, Lille, France
- 3 Department of Surgical, Oscar Lambret Center, Lille, France
- 4 CHU Lille, ULR 2694 - Metrics: Evaluation des Technologies de Santé et des Pratiques Médicales, University of Lille, Lille, France
- 5 Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA
Received: November 15, 2023 Accepted: October 15, 2024 Published: November 18, 2024
https://doi.org/10.18632/aging.206149How to Cite
Copyright: © 2024 Srour et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Aging of the epidermis partially occurs as a consequence of epidermal cell senescence, a non-proliferative state in which cells remain metabolically active and acquire changes in their secretome. We previously reported that senescent normal human epidermal keratinocytes (NHEKs) have two opposite outcomes: either cell death by excess of autophagic activity or escape from senescence to give rise to post-senescence neoplastic emerging (PSNE) cells. In this study, we investigated the role of PTGS2, the inducible enzyme of the prostaglandin biosynthesis pathway, in the onset of NHEK senescence and in the switch from senescence to pre-transformation. We provide evidence that the PTGS2/PGE2/EP4 pathway plays a critical role in NHEK senescence as well as in senescence escape. We show that treating proliferating NHEKs with prostaglandin E2 (PGE2) or with an agonist of one of its receptors, EP4, induced the establishment of the senescent phenotype, according to several markers including the senescence-associated β-galactosidase activity. Conversely, treating already senescent NHEKs with an antagonist of EP4, or knocking-down PTGS2 by siRNA resulted in the decrease of the percentage of senescence-associated β-galactosidase-positive cells. We also demonstrate that the PSNE frequency was significantly decreased upon PTGS2 silencing by siRNA, pharmacological PTGS2 inhibition, or treatment by an EP4 antagonist, while on the contrary treatments with PGE2 or EP4 agonist increased the PSNE frequency. These results indicate that the PTGS2/PGE2/EP4 pathway is required to induce and maintain the senescent phenotype of NHEKs, and that PGE2 level is a potential determinant of the initial steps of the age-related oncogenic process.
Abbreviations
PTGS2: prostaglandin-endoperoxide synthase 2; PG: prostaglandin; PSNE: post-senescence neoplastic escape; EP 1 to 4: prostaglandin receptor 1 to 4; SA-β-Gal: senescence-associated β-galactosidase; NHEK: normal human epidermal keratinocyte; SASP: senescence-associated secretory phenotype; PGE2: prostaglandin E2; PGH2: prostaglandin H2; PGD2: prostaglandin D2; PGF2α: prostaglandin F2alpha; NSAIDs: non-steroidal anti-inflammatory drugs; TX: thromboxane; MnSOD: manganese superoxide dismutase; GPX4: glutathioneperoxidase 4; ROS: reactive oxygen species; H2DCFDA: Dichlorodihydrofluorescein-diacetate; CM: conditioned medium; NHDF: Normal human dermal fibroblast; SCC: squamous cell carcinoma; AK: actinic keratoses; MMP: matrix metalloprotease.