Identification of thioredoxin-interacting protein (TXNIP) as a downstream target for IGF1 action

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-01, Vol.115 (5), p.1045-1050
• Main Authors: Nagaraj, Karthik, Lapkina-Gendler, Lena, Sarfstein, Rive, Gurwitz, David, Pasmanik-Chor, Metsada, Laron, Zvi, Yakar, Shoshana, Werner, Haim
• Format: Article
• Language: English
• Subjects: Abnormalities; Animals; Biological Sciences; Biomarkers; Cancer; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Diagnostic systems; Endocrine system; Epidemiology; Gene Expression; Genes; Genetics; Genomic analysis; Glucose; Glucose - metabolism; Growth disorders; Growth hormones; Humans; Insulin; Insulin - metabolism; Insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Laron Syndrome - genetics; Laron Syndrome - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - prevention & control; Oxidative Stress; Patients; Promoter Regions, Genetic; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Supplements; Thioredoxin; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1715930115

Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is the best-characterized entity among the congenital insulinlike growth factor 1 (IGF1) deficiencies. Life-long exposure to minute endogenous IGF1 levels is linked to low stature as well as a number of endocrine and metabolic abnormalities. While elevated IGF1 is correlated with increased cancer incidence, epidemiological studies revealed that patients with LS do not develop tumors. The mechanisms associated with cancer protection in LS are yet to be discovered. Recent genomic analyses identified a series of metabolic genes that are overrepresented in patients with LS. Given the augmented expression of these genes in a low IGF1 milieu, we hypothesized that they may constitute targets for IGF1 action. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular redox control by thioredoxin. TXNIP serves as a glucose and oxidative stress sensor, being commonly silenced by genetic or epigenetic events in cancer cells. Consistent with its enhanced expression in LS, we provide evidence that TXNIP gene expression is negatively regulated by IGF1. These results were corroborated in animal studies. In addition, we show that oxidative and glucose stresses led to marked increases in TXNIP expression. Supplementation of IGF1 attenuated TXNIP levels, suggesting that IGF1 exerts its antiapoptotic effect via inhibition of TXNIP. Augmented TXNIP expression in LS may account for cancer protection in this condition. Finally, TXNIP levels could be potentially useful in the clinic as a predictive or diagnostic biomarker for IGF1R-targeted therapies.