FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction.

Katarzyna Nowak,Hugo Stocker,Avantika Gupta,Norbert Perrimon

doi:10.1371/journal.pgen.1007347

Abstract

TORC1, a central regulator of cell survival, growth, and metabolism, is activated in a variety of cancers. Loss of the tumor suppressors PTEN and Tsc1/2 results in hyperactivation of TORC1. Tumors caused by the loss of PTEN, but not Tsc1/2, are often malignant and have been shown to be insensitive to nutrient restriction (NR). In Drosophila, loss of PTEN or Tsc1 results in hypertrophic overgrowth of epithelial tissues under normal nutritional conditions, and an enhanced TORC1-dependent hyperplastic overgrowth of PTEN mutant tissue under NR. Here we demonstrate that epithelial cells lacking Tsc1 or Tsc2 also acquire a growth advantage under NR. The overgrowth correlates with high TORC1 activity, and activating TORC1 downstream of Tsc1 by overexpression of Rheb is sufficient to enhance tissue growth. In contrast to cells lacking PTEN, Tsc1 mutant cells show decreased PKB activity, and the extent of Tsc1 mutant overgrowth is dependent on the loss of PKB-mediated inhibition of the transcription factor FoxO. Removal of FoxO function from Tsc1 mutant tissue induces massive hyperplasia, precocious differentiation, and morphological defects specifically under NR, demonstrating that FoxO activation is responsible for restricting overgrowth of Tsc1 mutant tissue. The activation status of FoxO may thus explain why tumors caused by the loss of Tsc1–in contrast to PTEN–rarely become malignant.

Highlights

In multicellular organisms, cellular and tissue growth is tightly coordinated with the local environment
Shortage of nutrients slows down cellular metabolism and protein synthesis, thereby restraining growth and proliferation of cells
Pre-cancerous cells deficient in specific tumor suppressors are resistant to these starvation-induced growth constraints, and instead gain a growth advantage over the surrounding tissue

Summary

Introduction

Cellular and tissue growth is tightly coordinated with the local environment. It is well established that target of rapamycin complex 1 (TORC1) and phosphatidylinositol 3-kinase (PI3K) coordinate tissue growth with nutrient availability, and their deregulation can induce growth irrespective of the nutritional status [4]. Activation of these pathways due to the loss of their negative regulators, tuberous sclerosis complex 1 and 2 (Tsc and Tsc2) and phosphatase and tensin homolog (PTEN), respectively, can cause cancer [5]. The inhibitory phosphorylation of Tsc, as well as the loss of either Tsc or Tsc, disrupts the GTPase-activating function of Tsc1/2 towards the small GTPase Rheb, which increases GTP-bound Rheb levels and activates TORC1 progrowth activity on the lysosomal membrane [6]. High TORC1 activity results in lowered PKB activation through an S6K-dependent negative feedback loop [6, 7], and in activation of FoxO-mediated transcription of growth-inhibitory genes [8]

Methods

Results

Discussion

Conclusion