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

Abstract

<p id="d10156880e260">Insulin-like growth factor 1 (IGF1) plays an important role in the regulation of metabolism and growth. Epidemiological studies revealed that IGF1 deficiency is associated with cancer protection. Genomic analyses conducted on patients with Laron syndrome (LS), a rare form of dwarfism linked to mutation of the growth hormone receptor, identified thioredoxin-interacting protein (TXNIP) as a downstream target for IGF1 action. <i>TXNIP</i> is a metabolic gene involved in redox regulation that can also function as a tumor suppressor. Data identify a regulatory link between the IGF1 signaling pathway and TXNIP. Elevated TXNIP levels in patients with LS may account for cancer protection in this pathology. Furthermore, TXNIP may constitute a biomarker to predict and/or monitor responsiveness to anti-IGF1R therapy. </p><p class="first" id="d10156880e266">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 <i>TXNIP</i> 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 <i>TXNIP</i> expression. Supplementation of IGF1 attenuated TXNIP levels, suggesting that IGF1 exerts its antiapoptotic effect via inhibition of <i>TXNIP</i>. Augmented <i>TXNIP</i> 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. </p>