Research Paper Volume 9, Issue 10 pp 2137—2162
SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes
- 1 Département de Biochimie et Médecine Moléculaire; Université de Montréal, Montréal, Québec H3C 3J7, Canada
- 2 Department of Biochemistry, Medicine & Oncology, Faculty of Medicine, McGill University, Goodman Cancer Research Centre, Montreal, Quebec H3A 1A3, Canada
- 3 Immunology Division, Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada
received: June 30, 2017 ; accepted: October 15, 2017 ; published: October 28, 2017 ;https://doi.org/10.18632/aging.101306
How to Cite
Copyright: Saint-Germain et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation of cellular senescence. In order to identify p53 target genes acting during the senescence response to oncogenic STAT5A, we characterized the transcriptome of STAT5A-expressing cells after SOCS1 inhibition. We identified a set of SOCS1-dependent p53 target genes that include several secreted proteins and genes regulating oxidative metabolism and ferroptosis. Exogenous SOCS1 was sufficient to regulate the expression of p53 target genes and sensitized cells to ferroptosis. This effect correlated with the ability of SOCS1 to reduce the expression of the cystine transporter SLC7A11 and the levels of glutathione. SOCS1 and SOCS1-dependent p53 target genes were induced during the senescence response to oncogenic STAT5A, RasV12 or the tumor suppressor PML. However, while SOCS1 sensitized cells to ferroptosis neither RasV12 nor STAT5A mimicked the effect. Intriguingly, PML turned cells highly resistant to ferroptosis. The results indicate different susceptibilities to ferroptosis in senescent cells depending on the trigger and suggest the possibility of killing senescent cells by inhibiting pathways that mediate ferroptosis resistance.