The LKB1–AMPK pathway: metabolism and growth control in tumour suppression

Shackelford, David B.; Shaw, Reuben J.

doi:10.1038/nrc2676

Cited by 1,629 publications

(1,679 citation statements)

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“…In line, AMPK activation induces relocalization of the glucose importer GLUT4 to the plasma membrane ( Figure 2) (Kurth-Kraczek et al, 1999). In addition, LKB1/AMPK signaling regulates factors involved in cell cycle regulation, survival and gene transcription (Figure 2) (Jansen et al, 2009;Shackelford and Shaw, 2009). One of the downstream effectors of AMPK is TSC2 as described in more detail below.…”

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confidence: 90%

“…In addition, mTorc1 hyperactivation has been observed in intestinal polyps of Lkb1 þ /À mice and PJS patients, indicating that mTORC1 is hyperactivated in PJS-associated hamartomas (Shaw et al, 2004;Shackelford and Shaw, 2009). Whether mTORC1 is hyperactivated in PJS-associated carcinomatous lesions as well, is yet to be determined.…”

Section: Hyperactive Mtorc1 In Lkb1/ampk/tsc-associated Lesionsmentioning

confidence: 99%

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The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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confidence: 90%

Section: Hyperactive Mtorc1 In Lkb1/ampk/tsc-associated Lesionsmentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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“…The tumor suppressor LKB1 (Shackelford and Shaw, 2009) phosphorylates and activates adenosine monophosphate-activated protein kinase (AMPK) at Thr 172 when the ratio of intracellular adenosine monophosphate/ATP increases (Shaw et al, 2004;Jones et al, 2005). Metformin-induced energy stress can be overcome by activating the LKB1-AMPK signaling pathway, which inhibits downstream targets, such as mammalian target of rapamycin complex 1, to downregulate processes that consume energy and activate processes that generate ATP, in keeping with the physiological role of AMPK as a key regulator of cellular energy homeostasis (Shaw et al, 2004;Jones et al, 2005;Hardie, 2007;Shackelford and Shaw, 2009). In addition, an AMPK-independent, rag GTPasedependent pathway by which metformin inhibits mammalian target of rapamycin complex 1 has recently been described (Kalender et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

et al. 2010

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Hypothesis-generating epidemiological research has suggested that cancer burden is reduced in diabetics treated with metformin and experimental work has raised questions regarding the role of direct adenosine monophosphate-activated protein kinase (AMPK)-mediated antineoplastic effects of metformin as compared with indirect effects attributable to reductions in circulating insulin levels in the host. We treated both tumor LKB1 expression and host diet as variables, and observed that metformin inhibited tumor growth and reduced insulin receptor activation in tumors of mice with diet-induced hyperinsulinemia, independent of tumor LKB1 expression. In the absence of hyperinsulinemia, metformin inhibited only the growth of tumors transfected with short hairpin RNA against LKB1, a finding attributable neither to an effect on host insulin level nor to activation of AMPK within the tumor. Further investigation in vitro showed that cells with reduced LKB1 expression are more sensitive to metformin-induced adenosine triphosphate depletion owing to impaired ability to activate LKB1-AMPK-dependent energy-conservation mechanisms. Thus, loss of function of LKB1 can accelerate proliferation in contexts where it functions as a tumor suppressor, but can also sensitize cells to metformin. These findings predict that any clinical utility of metformin or similar compounds in oncology will be restricted to subpopulations defined by host insulin levels and/or loss of function of LKB1.

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“…5e, f). Knockdown of the upstream AMPK kinase Ca 2+ -calmodulin-dependent protein kinase kinase (CaMKK2) 19,20 , but not liver kinase B1 (LKB1) 21 , decreased oleate-stimulated p-AMPK (Extended Data Fig. 5g).…”

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An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

226

237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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The LKB1–AMPK pathway: metabolism and growth control in tumour suppression

Cited by 1,629 publications

References 204 publications

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

An obligatory role for neurotensin in high-fat-diet-induced obesity

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