AMPK: A Contextual Oncogene or Tumor Suppressor?

Liang, Jiyong; Mills, Gordon B.

doi:10.1158/0008-5472.can-12-3876

Cited by 222 publications

(216 citation statements)

References 74 publications

(93 reference statements)

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“…We focused on AMPK␣ and mTOR, two opposing regulators of the autophagic pathway (61). When activated, AMPK␣, the master nutrient-sensing enzyme, binds and phosphorylates ULK1, a key kinase in the initiation of this process (53,62).…”

Section: Discussionmentioning

confidence: 99%

Endorepellin-evoked Autophagy Contributes to Angiostasis

Goyal

Gubbiotti

Chery

et al. 2016

Journal of Biological Chemistry

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Endorepellin, the C-terminal domain of perlecan, is an angiostatic molecule that acts as a potent inducer of autophagy via its interaction with VEGFR2. In this study, we examined the effect of endorepellin on endothelial cells using atomic force microscopy. Soluble endorepellin caused morphological and biophysical changes such as an increase in cell surface roughness and cell height. Surprisingly, these changes were not accompanied by alterations in the endothelial cell elastic modulus. We discovered that endorepellin-induced autophagic flux led to co-localization of mammalian target of rapamycin with LC3-positive autophagosomes. Endorepellin functioned upstream of AMPactivated kinase ␣, as compound C, an inhibitor of AMP-activated kinase ␣, abrogated endorepellin-mediated activation and co-localization of Beclin 1 and LC3, thereby reducing autophagic progression. Functionally, we discovered that both endorepellin and Torin 1, a canonical autophagic inducer, blunted ex vivo angiogenesis. We conclude that autophagy is a novel mechanism by which endorepellin promotes angiostasis independent of nutrient deprivation.

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Section: Discussionmentioning

confidence: 99%

Endorepellin-evoked Autophagy Contributes to Angiostasis

Goyal

Gubbiotti

Chery

et al. 2016

Journal of Biological Chemistry

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“…AMPK is a heterotrimeric enzyme that monitors the energy status and maintains energy homeostasis under metabolic stress by activating catabolic processes and inhibiting anabolic processes (9). However, the role of AMPK in metabolic transformation is still unclear, as both oncogenic and tumor suppressor functions have been reported (10). Interestingly, FLCN and its binding partner FLCN-interacting protein (FNIP) are known to interact with AMPK (11,12).…”

Section: Introductionmentioning

confidence: 99%

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

et al. 2014

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The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPKdependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.

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“…AMP-activated protein kinase (AMPK) activators and inhibitors are under investigation as novel cancer drugs (Liang and Mills, 2013). However, the different functions of AMPK signaling suggest an ambivalent role in oncogenic transformation.…”

Section: Introductionmentioning

confidence: 99%

Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib

et al. 2014

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OBJECTIVES: The therapeutic scheme for non-small cell lung cancer (NSCLC) patients can be improved if adapted to the individual response. For example, 60-70% of adenocarcinoma patients show response to EGFR-tyrosine kinase inhibitors in the presence of mutated EGFR. We searched for additional target molecules involved in the action of the EGFR-tyrosine kinase inhibitor erlotinib in the absence of EGFR mutations, which might be suitable for combinatorial therapy approaches. MATERIALS AND METHODS: Erlotinib-response associated proteins were investigated in patient-derived NSCLC mouse xenografts by reverse-phase protein array technology (RPPA) and Western blotting. A combinatorial treatment approach was carried out in NSCLC cell lines and H1299 mouse xenografts, and subsequently analyzed for consequences in cell growth and signal transduction. RESULTS: AMP-activated protein kinase (AMPK) expression was increased in erlotinib responders before and after treatment. In a combinatorial approach, activation of AMPK by A-769662 and erlotinib treatment showed a synergistic effect in cell growth reduction and apoptosis activation in H1299 cells compared to the single drugs. AMPK pathway analyses revealed an effective inhibition of mTOR signaling by drug combination. In H1299 xenografts, the tumor size was significantly decreased after combinatorial treatment. CONCLUSION: Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models

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AMPK: A Contextual Oncogene or Tumor Suppressor?

Cited by 222 publications

References 74 publications

Endorepellin-evoked Autophagy Contributes to Angiostasis

Endorepellin-evoked Autophagy Contributes to Angiostasis

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib

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