Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila.

Susumu Hirabayashi,Ross L Cagan

doi:10.7554/elife.08501

Abstract

Cancer cells demand excessive nutrients to support their proliferation but how cancer cells sense and promote growth in the nutrient favorable conditions remain incompletely understood. Epidemiological studies have indicated that obesity is a risk factor for various types of cancers. Feeding Drosophila a high dietary sugar was previously demonstrated to not only direct metabolic defects including obesity and organismal insulin resistance, but also transform Ras/Src-activated cells into aggressive tumors. Here we demonstrate that Ras/Src-activated cells are sensitive to perturbations in the Hippo signaling pathway. We provide evidence that nutritional cues activate Salt-inducible kinase, leading to Hippo pathway downregulation in Ras/Src-activated cells. The result is Yorkie-dependent increase in Wingless signaling, a key mediator that promotes diet-enhanced Ras/Src-tumorigenesis in an otherwise insulin-resistant environment. Through this mechanism, Ras/Src-activated cells are positioned to efficiently respond to nutritional signals and ensure tumor growth upon nutrient rich condition including obesity.

Highlights

The prevalence of obesity is increasing globally
While most tissues of animals fed HDS displayed insulin resistance, Ras/Src-activated tumors retained insulin pathway sensitivity and exhibited an increased ability to import glucose. This is reflected by increased expression of the Insulin Receptor (InR), which was activated through an increase in canonical Wingless (Wg)/dWnt signaling that resulted in evasion of diet-mediated insulin
Mitogenic effects of insulin are preserved but are enhanced in Ras/Src-activated cells in the presence of organismal insulin resistance. These studies provide an outline for a new mechanism by which tumors evade insulin resistance, but several questions remain: (i) how Ras/Src-activated cells sense the organism’s increased insulin levels, (ii) how nutrient availability is converted into growth signals, and (iii) the trigger for increased Wg protein levels, a key mediator that promotes evasion of insulin resistance and enhanced Ras/Srctumorigenesis consequent to HDS

Summary

Introduction

The prevalence of obesity is increasing globally. Obesity impacts whole-body homeostasis and is a risk factor for severe health complications including type 2 diabetes and cardiovascular disease. Mitogenic effects of insulin are preserved but are enhanced in Ras/Src-activated cells in the presence of organismal insulin resistance These studies provide an outline for a new mechanism by which tumors evade insulin resistance, but several questions remain: (i) how Ras/Src-activated cells sense the organism’s increased insulin levels, (ii) how nutrient availability is converted into growth signals, and (iii) the trigger for increased Wg protein levels, a key mediator that promotes evasion of insulin resistance and enhanced Ras/Srctumorigenesis consequent to HDS. In this manuscript, we identify the Hippo pathway effector Yorkie (Yki) as a primary source of increased Wg expression in diet-enhanced Ras/Src-tumors. These mechanisms act as a feedforward cassette that promotes tumor progression in dietary rich conditions, evading an otherwise insulin resistant state

Results

Discussion

Materials and methods