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

作者：Shackelford David B; Vasquez Debbie S; Corbeil Jacqueline; Wu Shulin; Leblanc Mathias; Wu Chin Lee; Vera David R; Shaw Reuben J^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(27): 11137-11142.

DOI：10.1073/pnas.0900465106

• AMPK
• FDG-PET
• glycolysis
• hamartoma
• polyposis

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-1 alpha transcription factor and its downstream transcriptional targets in an rapamycin-suppressible manner. The HIF-1 alpha 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-1 alpha, and GLUT1 levels. Furthermore, like HIF-1 alpha 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.

• 出版日期2009-7-7