NGAL Mediates Anaplastic Thyroid Carcinoma Cells survival Through FAS/CD95 Inhibition

Endocrinology. 2023 Dec 13:bqad190. doi: 10.1210/endocr/bqad190. Online ahead of print.ABSTRACTNeutrophil Gelatinase-Associated Lipocalin (NGAL), a siderophore-mediated iron binding protein, is highly expressed in human anaplastic thyroid carcinomas (ATC) where it plays pleiotropic pro-tumorigenic roles including that of pro-survival protein. Here we show that NGAL inhibits FAS/CD95 death receptor to control ATC cells survival. FAS/CD95 expression in human specimens from ATC patients and in ATC-derived cell lines negatively correlate with NGAL expression. Silencing of NGAL in ATC cells leads to FAS/CD95 up-regulation, whereas NGAL over-expression determines the opposite effect. As a result, an agonist anti-FAS/CD95 antibody induces cell death in NGAL-silenced cells while it is ineffective on NGAL-overexpressing cells. Interestingly, the inhibitory activity of NGAL on FAS/CD95 is due to its iron-carrier property given that perturbing iron homeostasis of NGAL proficient as well deficient ATC cells directly influences FAS/CD95 expression. Accordingly, conditioned media containing a mutant form of NGAL unable to bind siderophores cannot rescue cells from FAS/CD95-dependent death, whereas NGAL wild type-containing conditioned media abolish the effects of the agonist antibody. We also find that down-regulation of FAS/CD95 expression is mediated by iron-dependent NGAL suppression of p53 transcriptional activity. Our results indicate that the NGAL contributes to ATC cells survival by...
Source: Endocrinology - Category: Endocrinology Authors: Source Type: research