5′-AMP-Activated Protein Kinase (AMPK) Is Induced by Low-Oxygen and Glucose Deprivation Conditions Found in Solid-Tumor Microenvironments

Laderoute, Keith R.; Amin, Khalid; Calaoagan, Joy M.; Knapp, Merrill; Le, Theresamai; Orduna, Juan; Foretz, Marc; Viollet, Benoı̂t

doi:10.1128/mcb.00166-06

Cited by 402 publications

(392 citation statements)

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“…12 It is activated by many stresses including hypoxia. 15 Therefore, we investigated the potential role of AMPK in hypoxia-induced autophagy using immortalized MEFs derived from either wild-type or AMPKa1a2 knockout embryos. The a subunits, which provide AMPK catalytic activity, were absent in these knockout cell lines as assessed by western blotting (Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

“…Activation of AMPK has been known to occur after exposure to hypoxia, independently of HIF. 15,16 Furthermore, the finding that the TSC2 null MEFs are also resistant to hypoxia-induced autophagy suggests that AMPK is working upstream of TSC2 and through mTOR in regulating the process. 41 The fact that AMPKa nullizygous MEFs were not completely resistant to autophagy raises the possibility of additional pathways converging at the core autophagic machinery.…”

Section: Discussionmentioning

confidence: 99%

“…14 Hypoxia is a potent stimulus of AMPK, which is independent of HIF activity, and can occur even before there are any detectable decreases in intracellular ATP levels. 15,16 Recent reports suggest that in addition to AMPK's role in regulating normal glycolytic and oxidative metabolism, it can also regulate cellular energy homeostasis through the autophagic recycling of intracellular components. 17,18 Macroautophagy (called autophagy hereafter) is a catabolic process involving the regulated digestion of cellular macromolecules and even whole organelles.…”

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Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L

et al. 2008

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Macroautophagy (called autophagy hereafter) is a catabolic process activated by various types of stress, most notably by nutrient deprivation. The autophagic degradation of intracellular macromolecules provides metabolic support for the cell; however, this physiological process can also initiate a form of cell death (type 2 programmed cell death). Here we report that oxygen deprivation can activate the autophagic pathway in human cancer cell lines. We observed that hypoxia induced distinct cellular changes characteristic of autophagy such as an increase in cytoplasmic acidic vesicles, and processing and cellular localization of microtubule-associated protein-1 light chain 3. Oxygen deprivation-induced autophagy did not require nutrient deprivation, hypoxia-inducible factor-1 (HIF-1) activity, or expression of the HIF-1 target gene BNIP3 (Bcl-2 adenovirus E1a nineteen kilodalton interacting protein 3) or BNIP3L (BNIP3 like protein). Hypoxia-induced autophagy involved the activity of 5 0 -AMP-activated protein kinase (AMPK). Finally, we determined that cells lacking the autophagy gene ATG5 were unable to activate the autophagic machinery in hypoxia, had decreased oxygen consumption and increased glucose uptake under hypoxia, had increased survival in hypoxic environments, and exhibited accelerated growth as xenografted tumors. Together, these findings suggest that the autophagic degradation of cellular macromolecules contributes to the energetic balance governed by AMPK, and that suppression of autophagy in transformed cells can increase both resistance to hypoxic stress and tumorigenicity. Low oxygen tension is a common characteristic of several pathophysiological conditions including cancer. Hypoxia in solid tumors is associated with resistance to radiotherapy and poor prognosis. 1 One consequence of tumor hypoxia can be cell death. 2,3 However, several groups have shown that in general tumor cells are well adapted to moderate hypoxia, provided that there are no additional stresses such as glucose deprivation. However, extreme hypoxia is able to activate apoptosis through a hypoxia-inducible factor-1 (HIF-1)-independent process. 4-6 Interestingly, forced normoxic expression of HIF-1 target gene BNIP3 (Bcl-2 adenovirus E1a nineteen kilodalton interacting protein 3) has been reported to cause mitochondrial dysfunction and cell death in some, but not all, experimental settings. 5,7,8 Recent studies have also implicated BNIP3 in ceramide-and arsenic trioxide-induced autophagy 9,10 and in a model of ischemia/reperfusion cell death. 11 5 0 -AMP-activated protein kinase (AMPK) is a major regulator of energy homeostasis. 12 Increases in the AMP/ ATP ratio lead to activation of AMPK, which in turn promotes energy-producing catabolic processes and attenuation of energy-consuming anabolic processes. 13 One major downstream pathway for this effect is through tuberous sclerosis complex (TSC) and mammalian target of rapamycin (mTOR). 14 Hypoxia is a potent stimulus of AMPK, which is independent of HIF activity, and can occur ...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L

et al. 2008

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“…The immortalized isogenic AMPKa wt and À/À MEFs were created by Dr. Keith Laderoute and are described in ref. (24). All cell lines were maintained in 175 cm 2 flasks in RPMI and supplemented with 5% (v/v) fetal bovine serum (FBS), 100 units/mL of penicillin, and 100 mg/mL of streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Phosphatidylinositol Ether Lipid Analogues Induce AMP-Activated Protein Kinase–Dependent Death in LKB1-Mutant Non–Small Cell Lung Cancer Cells

et al. 2008

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Loss of function of the tumor suppressor LKB1 occurs in 30% to 50% of lung adenocarcinomas. Because LKB1 activates AMP-activated protein kinase (AMPK), which can negatively regulate mTOR, AMPK activation might be desirable for cancer therapy. However, no known compounds activate AMPK independently of LKB1 in vivo, and the usefulness of activating AMPK in LKB1-mutant cancers is unknown. Here, we show that lipid-based Akt inhibitors, phosphatidylinositol ether lipid analogues (PIA), activate AMPK independently of LKB1. PIAs activated AMPK in LKB1-mutant non-small cell lung cancer (NSCLC) cell lines with similar concentration dependence as that required to inhibit Akt. However, AMPK activation was independent of Akt inhibition. AMPK activation was a major mechanism of mTOR inhibition. To assess whether another kinase capable of activating AMPK, CaMKKB, contributed to PIA-induced AMPK activation, we used an inhibitor of CaMKK, STO-609. STO-609 inhibited PIA-induced AMPK activation in LKB1-mutant NSCLC cells, and delayed AMPK activation in wild-type LKB1 NSCLC cells. In addition, AMPK activation was not observed in NSCLC cells with mutant CaMKKB, suggesting that CaMKKB contributes to PIA-induced AMPK activation in cells. AMPK activation promoted PIA-induced cytotoxicity because PIAs were less cytotoxic in AMPKAÀ/À murine embryonic fibroblasts or LKB1-mutant NSCLC cells transfected with mutant AMPK. This mechanism was also relevant in vivo. Treatment of LKB1-mutant NSCLC xenografts with PIA decreased tumor volume by f50% and activated AMPK. These studies show that PIAs recapitulate the activity of two tumor suppressors (PTEN and LKB1) that converge on mTOR. Moreover, they suggest that PIAs might have utility in the treatment of LKB1-mutant lung adenocarcinomas.

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“…2016. 46: 929-940 have been established [6][7][8][9], however the understanding of how the microenvironmental stresses interfere MHC class I antigen processing and CD8 + T-cell responses is incomplete. MHC class I molecules are expressed on most nucleated cells and determine the outcome of CD8 + T-cell mediated immune surveillance.…”

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Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8⁺ T‐cell recognition of stressed cells

et al. 2016

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Hypoxia and glucose deprivation are often observed in the microenvironment surrounding solid tumors in vivo. However, how they interfere with MHC class I antigen processing and CD8 + T-cell responses remains unclear. In this study, we analyzed the production of antigenic peptides presented by classical MHC class I in mice, and showed that it is quantitatively decreased in the cells exposed to either hypoxia or glucose deprivation. In addition, we unexpectedly found increased surface expression of HLA-E in human and Qa-1 in mouse tumor cells exposed to combined oxygen and glucose deprivation. The induced Qa-1 on the stressed tumor model interacted with an inhibitory NKG2/CD94 receptor on activated CD8 + T cells and attenuated their specific response to the antigen. Our results thus suggest that microenvironmental stresses modulate not only classical but also nonclassical MHC class I presentation, and confer the stressed cells the capability to escape from the CD8 + T-cell recognition.Keywords: Antigen presentation r Glucose deprivation hypoxia r HLA-E r MHC class I r Microenvironmental stress r Qa-1 Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSolid tumors provide a special microenvironment that alters the biological aspects of the cells within [1]. Because of aberrant Correspondence: Dr. Takayuki Kanaseki e-mail: kanaseki@sapmed.ac.jp and disorganized vasculature, tumor cells inside a mass are often exposed to chronic hypoxia, which induces stress-related gene expression as well as resistance to apoptosis, radiation, and chemotherapy [2,3]. Moreover, tumor cells predominantly use the tricarboxylic acid cycle rather than oxidative phosphorylation for energy production (Warburg effect) and they are exposed to severe glucose deprivation [4,5]. The biological adaptation models of tumor cells to survive under such combined-stress condition C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 930Takanori Sasaki et al. Eur. J. Immunol. 2016. 46: 929-940 have been established [6][7][8][9], however the understanding of how the microenvironmental stresses interfere MHC class I antigen processing and CD8 + T-cell responses is incomplete. MHC class I molecules are expressed on most nucleated cells and determine the outcome of CD8 + T-cell mediated immune surveillance. They are classified into highly polymorphic classical MHC class I molecules and nonpolymorphic nonclassical MHC class I molecules. The classical MHC I molecules on the surface present short peptides originating from endogenous self or foreign proteins and form complexes with a diverse set of peptide (pMHC I) [10,11]. Such short peptides are generally 8-10-mer in length and conserve anchor residues that locate at discrete positions, allowing the peptide to be bound to MHC I molecules [12]. The peptides are produced by MHC I antigen processing that begins in the cytosol and continues in the ER where the precursor peptides are optimized for binding and finally load...

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5′-AMP-Activated Protein Kinase (AMPK) Is Induced by Low-Oxygen and Glucose Deprivation Conditions Found in Solid-Tumor Microenvironments

Cited by 402 publications

References 57 publications

Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L

Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L

Phosphatidylinositol Ether Lipid Analogues Induce AMP-Activated Protein Kinase–Dependent Death in LKB1-Mutant Non–Small Cell Lung Cancer Cells

Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8⁺ T‐cell recognition of stressed cells

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5′-AMP-Activated Protein Kinase (AMPK) Is Induced by Low-Oxygen and Glucose Deprivation Conditions Found in Solid-Tumor Microenvironments

Cited by 402 publications

References 57 publications

Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L

Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L

Phosphatidylinositol Ether Lipid Analogues Induce AMP-Activated Protein Kinase–Dependent Death in LKB1-Mutant Non–Small Cell Lung Cancer Cells

Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8+ T‐cell recognition of stressed cells

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Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8⁺ T‐cell recognition of stressed cells