Nrf2 prevents Notch-induced insulin resistance and tumorigenesis in mice
Dionysios V. Chartoumpekis, Yoko Yagishita, Marco Fazzari, Dushani L. Palliyaguru, Uma N.M. Rao, Apostolos Zaravinos, Nicholas K.H. Khoo, Francisco J. Schopfer, Kurt R. Weiss, George K. Michalopoulos, Ian Sipula, Robert M. O’Doherty, Thomas W. Kensler, Nobunao Wakabayashi
Dionysios V. Chartoumpekis, Yoko Yagishita, Marco Fazzari, Dushani L. Palliyaguru, Uma N.M. Rao, Apostolos Zaravinos, Nicholas K.H. Khoo, Francisco J. Schopfer, Kurt R. Weiss, George K. Michalopoulos, Ian Sipula, Robert M. O’Doherty, Thomas W. Kensler, Nobunao Wakabayashi
View: Text | PDF
Research Article Metabolism Oncology

Nrf2 prevents Notch-induced insulin resistance and tumorigenesis in mice

Abstract

Insulin resistance is associated with increased incidence and enhanced progression of cancers. However, little is known about strategies that can effectively ameliorate insulin resistance and consequently halt cancer progression. Herein, we propose that the transcription factor Nrf2 (also known as Nfe2l2) may be such a target, given its central role in disease prevention. To this end, we developed a mouse that overexpresses the Notch intracellular domain in adipocytes (AdNICD), leading to lipodystrophy-induced severe insulin resistance and subsequent development of sarcomas, as a model reflecting that Notch signaling is deregulated in cancers and shows positive associations with insulin resistance and fatty liver disease in humans. Nrf2 pathway activation was achieved by knocking down Keap1, a repressor of Nrf2, in the AdNICD background. Constitutively enhanced Nrf2 signaling in this setting led to prevention of hepatic steatosis, dyslipidemia, and insulin resistance by repressing hepatic lipogenic pathways and restoration of the hepatic fatty acid profile to control levels. This protective effect of Nrf2 against diabetes extended to significant reduction and delay in sarcoma incidence and latency. Our study highlights that the Nrf2 pathway, which has been induced by small molecules in clinical trials, is a potential therapeutic target against insulin resistance and subsequent risk of cancer.

Authors

Dionysios V. Chartoumpekis, Yoko Yagishita, Marco Fazzari, Dushani L. Palliyaguru, Uma N.M. Rao, Apostolos Zaravinos, Nicholas K.H. Khoo, Francisco J. Schopfer, Kurt R. Weiss, George K. Michalopoulos, Ian Sipula, Robert M. O’Doherty, Thomas W. Kensler, Nobunao Wakabayashi

×

Figure 9

NICD-driven soft-tissue sarcomas show the pathology signature of liposarcomas and increased genomic instability.

Options: View larger image (or click on image) Download as PowerPoint
NICD-driven soft-tissue sarcomas show the pathology signature of liposar...
(A) Location of tumors in AdNICD and Keap1KD:AdNICD mice, expressed as percentages of the total number of tumors. n = 61 AdNICD (4 mice had 2 parallel tumors); n = 7, Keap1KD:AdNICD. All tumors were detected in subcutaneous areas of the mice, with the exception of 1 in the AdNICD mouse, which was located in the perirenal area. (B) Evaluation summary of staining of sections of 15 AdNICD tumors with pankeratin, Cd34, desmin, and S100 antibodies. Mice bearing these tumors had a median age of 7 months. (C) Mapping on the chromosomes of highly significant represented SNPs and indels (P < 0.005) among the 5 tumor samples compared with their matched nontumor controls (tails). The “lollipops” indicate their location on the chromosome. Blue lollipops indicate SNPs and green lollipops indicate indels. Only the chromosomes where SNPs or indels were detected are shown. (D) Summary of the overlapping gains (blue lollipops) and losses (gray lollipops) that were detected in at least 4 tumor samples, as determined by analysis of copy number variation (CNV), compared tumor with nontumor-matched controls (tail) using exome sequencing. The thick black line on the chromosome indicates the relative size (length) of each detected CNV. CNVs on chromosomes 3, 4, 6, and 15 were detected in all 5 tumors, while those on 16 and 19 were detected in 4 of 5 tumors. Only gains or losses larger than 1 kb with probability ≥50% are depicted at their starting position on the chromosome. Only the chromosomes where gains or losses were detected are shown.