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

Abstract

<div><p>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 <i>Drosophila</i>, loss of PTEN or Tsc1 results in hypertrophic overgrowth of epithelial tissues under normal nutritional conditions, and an enhanced TORC1-dependent hyperplastic overgrowth of <i>PTEN</i> 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 <i>Rheb</i> is sufficient to enhance tissue growth. In contrast to cells lacking PTEN, <i>Tsc1</i> mutant cells show decreased PKB activity, and the extent of <i>Tsc1</i> mutant overgrowth is dependent on the loss of PKB-mediated inhibition of the transcription factor FoxO. Removal of FoxO function from <i>Tsc1</i> mutant tissue induces massive hyperplasia, precocious differentiation, and morphological defects specifically under NR, demonstrating that FoxO activation is responsible for restricting overgrowth of <i>Tsc1</i> 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.</p></div