LKB1 specifies neural crest cell fates through pyruvate-alanine cycling

Radu, Aurelian; Torch, Sakina; Fauvelle, F.; Pernet‐Gallay, Karin; Lucas, Anthony; Blervaque, Renaud; Delmas, Véronique; Schlattner, Uwe; Lafanechère, Laurence; Hainaut, Pierre; Tricaud, Nicolas; Pingault, Véronique; Bondurand, Nadège; Bardeesy, Nabeel; Larue, Lionel; Thibert, Chantal; Billaud, Marc

doi:10.1126/sciadv.aau5106

Cited by 17 publications

(40 citation statements)

References 84 publications

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“…This result highlights the crucial role of gluconeogenesis deregulation in the development of the lethal phenotype in mutant mice. Interestingly, recent studies have identified transaminases as effectors of other metabolic functions of Lkb1 involved in the epigenetic reprogramming occurring during malignant transformation 44 , or during the glial fate specification of neural crest cells 45 . Together with our data, these results highlight a key unsuspected role of aminotransferases in Lkb1 function.…”

Section: Discussionmentioning

confidence: 99%

Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

et al. 2020

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Excessive glucose production by the liver is a key factor in the hyperglycemia observed in type 2 diabetes mellitus (T2DM). Here, we highlight a novel role of liver kinase B1 (Lkb1) in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect is observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion is associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic, proteomic and pharmacological approaches, we identify the aminotransferases and specifically Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.

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Section: Discussionmentioning

confidence: 99%

Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

et al. 2020

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“…Furthermore, the role of alanine has been highlighted in cancer [66]. Although there is no solid evidence of its role in promoting AML, it is supposed to act in tandem wilth the liver kinase LKB1 [69]. Leukemic stem cells (LSCs) are an essential area of research that has been discussed over the years with regard to AML [93].…”

Section: Discussionmentioning

confidence: 99%

“…However, the liver kinase B1 (LKB1) is an important -master kinase‖ of metabolism in various cancers, and is thought, for the most part, to act as a tumor suppressor in AML by downregulating the mTOR pathway and subsequently decreasing cell growth and survival [68]. Recently, it was found that LKB1 regulates ALT activity and thus the pyruvate-alanine conversion in neural crest cells, in a pathway that relies on mTOR [69]. As LKB1 is highly active under nutrient-deficient conditions in AML, it could potentially affect alanine metabolism by regulating ALT activity in a similar manner, although this premise remains hypothetical.…”

Section: Alanine Metabolism In Cancersmentioning

confidence: 99%

Amino Acid Metabolism in Acute Myeloid Leukemia

Mossuz¹,

Mondet²,

Rajesh³

2021

Immunology and Cancer Biology

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The role of metabolic alterations in cancer cells has been discussed and clarified over the years. Researchers focused on key metabolites and the mechanisms they initiate in cancer. Acute myeloid leukemia (AML) is one such cancer that is dependent on certain metabolites and the pathways they trigger. www.videleaf.com Even though several advances have been made in understanding the mechanisms underlying the initiation and progression of AML, therapies targeted toward these mechanisms, although potent, do not always achieve the desired effect. Hence, studying the metabolic alterations in AML is one of the many approaches researchers currently employ in order to glean a deeper understanding of the intricacies that govern this cancer. Amino acids are crucial players in AML. They trigger several cell survival and replication processes, as well as modulate key epigenetic processesall of which are critical in carcinogenesis. Moreover, several amino acids have been found to play a role in the maintenance of leukemic stem cells, which are correlated to poor prognosis in AML. The role of a few amino acids in AML are highlighted in this review.

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“…LKB1-deficient adult mice displayed exhaustion of the HSC pool. LKB1 is also involved in the regulation of stem cell fates, such as the induced pluripotent stem (iPS) cell-derived mesenchymal stem cells, neural crest cells, and intestinal stem cells [ [116] , [117] , [118] ]. It is believed that LKB1 plays an essential role in stem cell homeostasis.…”

Section: The Double-edged Sword Behavior Of Lkb1mentioning

confidence: 99%

LKB1 deficiency-induced metabolic reprogramming in tumorigenesis and non-neoplastic diseases

Zhang

Meng

Sun

et al. 2021

Molecular Metabolism

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Background Live kinase B1 (LKB1) is a tumor suppressor that is mutated in Peutz-Jeghers syndrome (PJS) and a variety of cancers. Lkb1 encodes serine-threonine kinase (STK) 11 that activates AMP-activated protein kinase (AMPK) and its 13 superfamily members, regulating multiple biological processes, such as cell polarity, cell cycle arrest, embryo development, apoptosis, and bioenergetics metabolism. Increasing evidence has highlighted that deficiency of LKB1 in cancer cells induces extensive metabolic alterations that promote tumorigenesis and development. LKB1 also participates in the maintenance of phenotypes and functions of normal cells through metabolic regulation. Scope of review Given the important role of LKB1 in metabolic regulation, we provide an overview of the association of metabolic alterations in glycolysis, aerobic oxidation, the pentose phosphate pathway (PPP), gluconeogenesis, glutamine, lipid, and serine induced by aberrant LKB1 signals in tumor progression, non-neoplastic diseases, and functions of immune cells. Major conclusions In this review, we summarize layers of evidence demonstrating that disordered metabolisms in glucose, glutamine, lipid, and serine caused by LKB1 deficiency promote carcinogenesis and non-neoplastic diseases. The metabolic reprogramming resulting from the loss of LKB1 confers cancer cells with growth or survival advantages. Nevertheless, it also causes a metabolic frangibility for LKB1-deficient cancer cells. The metabolic regulation of LKB1 also plays a vital role in maintaining cellular phenotype in the progression of non-neoplastic diseases. In addition, lipid metabolic regulation of LKB1 plays an important role in controlling the function, activity, proliferation, and differentiation of several types of immune cells. We conclude that in-depth knowledge of metabolic pathways regulated by LKB1 is conducive to identifying therapeutic targets and developing drug combinations to treat cancers and metabolic diseases and achieve immunoregulation.

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LKB1 specifies neural crest cell fates through pyruvate-alanine cycling

Cited by 17 publications

References 84 publications

Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

Lkb1 suppresses amino acid-driven gluconeogenesis in the liver

Amino Acid Metabolism in Acute Myeloid Leukemia

LKB1 deficiency-induced metabolic reprogramming in tumorigenesis and non-neoplastic diseases

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