mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome

Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11137-42. doi: 10.1073/pnas.0900465106. Epub 2009 Jun 18.

Abstract

Peutz-Jeghers syndrome (PJS) is a familial cancer disorder due to inherited loss of function mutations in the LKB1/ STK11 serine/threonine kinase. PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life, and demonstrate an increased predisposition toward the development of a number of additional malignancies. Among mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice. Consistent with a central role for mTORC1 in these tumors, rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1+/- mice. However, the key targets of mTORC1 in LKB1-deficient tumors remain unknown. We demonstrate here that these polyps, and LKB1- and AMPK-deficient mouse embryonic fibroblasts, show dramatic up-regulation of the HIF-1alpha transcription factor and its downstream transcriptional targets in an rapamycin-suppressible manner. The HIF-1alpha targets hexokinase II and Glut1 are up-regulated in these polyps, and using FDG-PET, we demonstrate that LKB1+/- mice show increased glucose utilization in focal regions of their GI tract corresponding to these gastrointestinal hamartomas. Importantly, we demonstrate that polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1alpha, and GLUT1 levels. Furthermore, like HIF-1alpha and its target genes, the FDG-PET signal in the GI tract of these mice is abolished by rapamycin treatment. These findings suggest a number of therapeutic modalities for the treatment and detection of hamartomas in PJS patients, and potential for the screening and treatment of the 30% of sporadic human lung cancers bearing LKB1 mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Glucose / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Peutz-Jeghers Syndrome / enzymology*
  • Peutz-Jeghers Syndrome / pathology*
  • Positron-Emission Tomography
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteins
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism
  • Tumor Burden / drug effects
  • Up-Regulation / drug effects

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Multiprotein Complexes
  • Proteins
  • Transcription Factors
  • Protein Kinases
  • Stk11 protein, mouse
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • Glucose
  • Sirolimus