Impact of the UPR/ATF6α pathway on UVB-induced senescence

Résumé

Facing up to the global challenge of ageing, cellular senescence is one of the most studied mechanisms to improve age-related physiological or pathological changes. Cellular senescence is known to be characterized by several biomarkers: morphological changes, SA-βgal activity, cell cycle arrest, DNA damage and senescence-associated secretory phenotype (SASP). However, the molecular pathways involved in the appearance of the senescent phenotype remain poorly understood. Recently, it has been proposed that endoplasmic reticulum (ER) stress and the Unfolded Protein Response (UPR) can be involved in the establishment of the senescent phenotype. The UPR is initiated by three sensors, PERK, IRE1α and ATF6α. Surprisingly, it has been determined that invalidating the ATF6α branch of the UPR pathway led to a regression of some senescent biomarkers in replicative senescent fibroblasts. However, the involvement of the UPR pathway in the induction of other types of senescence, and on the composition and effects of the SASP, is not yet clearly established. Therefore, we assessed the impact of the ATF6α invalidation by RNA interference in UVB-induced senescence in normal human dermal fibroblasts (NHDFs). In the first part, different classical biomarkers of senescence were assessed upon UVB exposures and ATF6α invalidation. Then, the expression of some specific SASP related genes was evaluated by RT-qPCR to highlight or not a modification of the SASP composition with the invalidation of ATF6α. Finally, as the SASP is known to have a potential paracrine pro-tumorigenic effect, we checked that conditioned medium harvested from premature senescent fibroblasts upon ATF6α invalidation does not promote the proliferation, migration or invasion of melanoma skin cancer cells. Our results displayed that ATF6α invalidation appeared to protect against morphological changes, SA-βgal activity, DNA damage and allowed to decrease the gene expression of the pro-inflammatory mediator IL6. In addition, the conditioned medium from NHDFs exposed to UVB revealed that ATF6α invalidation slightly decreased the proliferation and migration of melanoma cells, but did not impact their invasion capacities. Collectively, these results revealed a potential role of ATF6α in the establishment of the senescent phenotype following repeated UVB exposures.

la date de réponse	17 janv. 2023
langue originale	Anglais
L'institution diplômante	Universite de Namur
Superviseur	Florence Debacq-Chainiaux (Promoteur)