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

Dulbecco Center for Cancer Research, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 07/2009; 106(27):11137-11142. DOI: 10.1073/pnas.0900465106

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

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Available from: David R Vera, Jul 07, 2015
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    • "Hypoxic cancer cells respond to low oxygen tension through the activation of the hypoxia-inducible factor 1a (HIF1) [16] [17] that, in turn, activates the expression of various hypoxia-response genes, such as those encoding for glucose transporters, metabolic enzymes , erythropoietin, and angiogenic factors [18]. Recently, it has been demonstrated that different oncogenic and tumor suppressor mutations found in a wide variety of human cancers can directly activate HIF1 and other enzymes involved in glucose metabolism independently of hypoxia [19] [20] [21] [22] [23] [24] [25] [26] [27] [28]. Together with hypoxia, metabolic stress is often observed in many cancer types [12] [29] [30] and represents a key hallmark of malignancy [31]. "
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    • "Specifically, the catalytic a-subunit of AMPK is activated by phosphorylation of Thr172 by one of three upstream kinases: liver kinase B1 (LKB1 or serine/threonine kinase 11 (STK11)), calmodulin-dependent protein kinase kinase-b, or TGF-b-activated-kinase 1 (Viollet et al, 2010). The LKB1 tissue-specific knockout mice revealed that LKB1 mediates AMPK activation in the majority of tissues (Shackelford et al, 2009). Although the major downstream target of LKB1 tumour suppressor is AMPK, LKB1 has at least 12 other substrates, which include members of the AMPK-related protein kinase subfamily, such as MARK1-4 (Lizcano et al, 2004). "
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    • "Our data are consistent with this since HIF-1 accumulates in the ctl-1, ctl-2, and ctl-3 mutant backgrounds to levels that are near the range of those seen with vhl-1(RNAi), while similar HIF-1 stabilization is observed by treatment of animals with 0.1% H 2 O 2 (Figure 4C). Somewhat unexpectedly, we did not note any effect of AMPK depletion on HIF-1 levels, contrary to findings reported in other contexts (Shackelford et al., 2009; Shaw, 2006; Brugarolas and Kaelin, 2004). We further assessed HIF-1 protein levels in catalase-deficient AMPK mutant dauers treated with 10 mM NAC, which resulted in a significant drop in HIF-1 levels (Figure 4D) that was reversed after a combined treatment of H 2 O 2 and NAC (Figure S4). "
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