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

Edited by Dennis A. Carson, University of California, San Diego, La Jolla, CA, and approved December 20, 2017 (received for review September 12, 2017)
January 16, 2018
115 (5) 1045-1050

Significance

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. TXNIP 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.

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.

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Acknowledgments

We thank Dr. Jay Ware for providing cell lines. This work was performed in partial fulfillment of the requirements for a PhD degree by K.N. at the Sackler Faculty of Medicine, Tel Aviv University. This research was supported by Grant 1403/14 from the Israel Science Foundation and Grant 20170079 from the Bernard Lieberman Foundation (Israel Cancer Association). H.W. is the incumbent of the Lady Davis Chair in Biochemistry (Tel Aviv University).

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 115 | No. 5
January 30, 2018
PubMed: 29339473

Classifications

Submission history

Published online: January 16, 2018
Published in issue: January 30, 2018

Keywords

  1. insulin-like growth factor 1
  2. IGF1 receptor
  3. TXNIP
  4. Laron syndrome

Acknowledgments

We thank Dr. Jay Ware for providing cell lines. This work was performed in partial fulfillment of the requirements for a PhD degree by K.N. at the Sackler Faculty of Medicine, Tel Aviv University. This research was supported by Grant 1403/14 from the Israel Science Foundation and Grant 20170079 from the Bernard Lieberman Foundation (Israel Cancer Association). H.W. is the incumbent of the Lady Davis Chair in Biochemistry (Tel Aviv University).

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Karthik Nagaraj
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
Lena Lapkina-Gendler
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
Rive Sarfstein
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
David Gurwitz
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
Metsada Pasmanik-Chor
Bioinformatics Unit, George Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel;
Zvi Laron
Endocrine and Diabetes Research Unit, Schneider Children’s Medical Center, 49292 Petah Tikva, Israel;
Shoshana Yakar
David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY;
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
Yoran Institute for Human Genome Research, Tel Aviv University, 69978 Tel Aviv, Israel

Notes

1
To whom correspondence should be addressed. Email: [email protected].
Author contributions: K.N., Z.L., and H.W. designed research; K.N., L.L.-G., R.S., and S.Y. performed research; D.G. contributed new reagents/analytic tools; K.N., L.L.-G., R.S., D.G., M.P.-C., Z.L., S.Y., and H.W. analyzed data; and H.W. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Identification of thioredoxin-interacting protein (TXNIP) as a downstream target for IGF1 action
    Proceedings of the National Academy of Sciences
    • Vol. 115
    • No. 5
    • pp. 823-E1075

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