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

Karthik Nagaraj, Lena Lapkina-Gendler, Rive Sarfstein, David Gurwitz, Metsada Pasmanik-Chor, Zvi Laron, Shoshana Yakar, Haim Werner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is the best-characterized entity among the congenital insulin-like 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.

Original languageEnglish
Pages (from-to)1045-1050
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number5
DOIs
StatePublished - 30 Jan 2018

Funding

FundersFunder number
Bernard Lieberman Foundation
Israel Cancer Association
Israel Science Foundation20170079

    Keywords

    • IGF1 receptor
    • Insulin-like growth factor 1
    • Laron syndrome
    • TXNIP

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