Cancer protection in Laron syndrome patients is associated with regulation of thioredoxin-interacting protein (TXNIP) in senescence

Background: Laron syndrome (LS) is a congenital autosomal recessive disorder caused by molecular defects in the growth hormone receptor (GHR) gene, leading to congenital IGF1 deficiency. Recent epidemiological studies reported that LS patients have a reduced risk of cancer development. Thioredoxin-interacting protein (TXNIP) plays an important role in redox homeostasis and glucose metabolism. In addition, TXNIP has been identified as a candidate tumor suppressor gene. The aim of our study was to investigate the involvement of the TXNIP gene product in the process of senescence.

Methods: Primary fibroblasts, 3T3L1 adipocytes, and HEK293 cells were used in this study. Real-time PCR (qRT-PCR) was carried out following hormonal treatments at different time points. Expression levels of receptors, proteins, and activation of signaling cascades were measured by Western immunoblotting. Beta-gal assays were carried out to assess senescence.

Results: Genomic analyses conducted on lymphoblastoid cell lines revealed that TXNIP mRNA levels in LS patients were several-fold higher than in healthy controls. In addition, qRT-PCR and Western blots revealed that IGF1 and insulin significantly downregulated TXNIP gene and protein expression in a time-dependent manner. Furthermore, beta-gal assays conducted upon TXNIP silencing revealed that under stress condition TXNIP regulates the process of senescence.

Conclusions: Our analyses have identified an important novel link between the TXNIP gene and the IGF1R signaling pathway, and the role of TXNIP in senescence with potential implications in cell homeostasis during oxidative and glucose stresses. Further studies will dissect the TXNIP-mediated mechanisms at the molecular and cellular levels.