Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia

Sujobert, Pierre; Poulain, Laury; Paubelle, Étienne; Zylbersztejn, Florence; Grenier, Adrien; Lambert, Mireille; Townsend, Elizabeth; Brusq, Jean-Marie; Nicodème, Edwige; Decrooqc, Justine; Nepstad, Ina; Green, Alexa S.; Mondesir, Johanna; Jacque, Nathalie; Christodoulou, Alexandra; DeSouza, Tiffany; Hermine, Olivier; Foretz, Marc; Viollet, Benoı̂t; Lacombe, Catherine; Mayeux, Patrick; Weinstock, David M.; Moura, Ivan C.; Bouscary, Didier; Tamburini, Jérôme

doi:10.1016/j.celrep.2015.04.063

Cited by 96 publications

(93 citation statements)

References 51 publications

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“…However, in cancers in which the net role effect of AMPK is growth suppression, specific and direct AMPK activators could be therapeutically more beneficial. In this regard, in a recent report, AMPK activation by relatively specific AMPK activators killed AML cells only with hyperactivated mTORC1 [193]. Interestingly, similar to our previous results [26], this study also found a disconnect between AMPK activation and mTOR suppression since AMPK activation did not inhibit mTORC1 in at least three AML cell lines and primary AML samples.…”

Section: Discussionsupporting

confidence: 89%

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Dasgupta

Chhipa

2016

Trends in Pharmacological Sciences

110

120

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AMP kinase (AMPK) is an evolutionarily conserved enzyme required for adaptive responses to various physiological and pathological conditions. AMPK executes numerous cellular functions, some of which are often perceived at odds with each other. While AMPK is essential for embryonic growth and development, its full impact in adult tissues is revealed under stressful situations that organisms face in the real world. Conflicting reports about its cellular functions, particularly in cancer, are intriguing and a growing number of AMPK activators are being developed to treat human diseases such as cancer and diabetes. Whether these drugs will have only context-specific benefits or detrimental effects in the treatment of human cancer will be a subject of intense research. Here we review the current state of AMPK research with an emphasis on cancer and discuss the yet unresolved context-dependent functions of AMPK in human cancer.

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Section: Discussionsupporting

confidence: 89%

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Dasgupta

Chhipa

2016

Trends in Pharmacological Sciences

110

120

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“…Cells (1x10 4 ) were incubated with acridine orange at 25˚C for 17 min, harvested with trypsin-EDTA, and then collected in phenol red-free growth medium (Thermo Fisher Scientific, Inc.). Green (510-530 nm) and red (650 nm) fluorescence emission from cells illuminated with blue (488 nm) excitation light was analyzed using FACS Calibur system using CellQuest software as mentioned above.…”

Section: Reagentsmentioning

confidence: 99%

“…The BCR RhoGEF and GTPase activating protein (BCR)-ABL proto-oncogene 1 nonreceptor tyrosine kinase (ABL) gene rearrangement is the main characteristic of CML, which expresses the oncogenic fusion protein BCR-ABL (2). BCR-ABL is a constitutively active tyrosine kinase, which activates multiple signaling pathways and consequently promotes malignant transformation, including uncontrolled cell proliferation (3), abnormal cell adhesion (4), and resistance to typical apoptotic inducer anti-leukemic drugs (5,6). Thus, formation of the BCR-ABL fusion gene serves an essential role in the pathogenesis of CML (7).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, mounting evidences have suggested that AMPK could be a target for tumor prevention and treatment (7). Previous studies have revealed that AMPK activators exhibit anti-leukemia effects in CML cells by triggering apoptosis and autophagy (3,4). Thus, the Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling identification and characterization of AMPK activators is important, and beneficial for the development of potential anti-leukemia drugs.…”

Section: Introductionmentioning

confidence: 99%

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Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling

Chen

Lin

et al. 2017

Oncol Lett

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Abstract. AMP-activated protein kinase (AMPK) is known as a pivotal regulator of cellular metabolism. Mounting evidences have demonstrated that AMPK activation exerts tumor suppressive activity on leukemia cells. The present study reported that adenine, an AMPK activator, triggers cell cycle arrest and autophagy of human chronic myelogenous leukemia K562 cells consequently suppressing cell viability. The present findings revealed that adenine treatment (4.0-8.0 mM) significantly inhibited the viability of K562 cells to 69.3±2.5% (24 h) and 53.4±2.1% (48 h) of the control. Flow cytometric analysis revealed that there was a significant accumulation in G 2 /M phase, but not sub-G 1 phase K562 cells following exposure to adenine. Additional investigation demonstrated that adenine treatments significantly increased the number of acidic vesicular organelles and the level of autophagosomal microtubule associated protein 1 light chain 3 α (LC3) marker. By contrast, cleavage of caspase-9, caspase-3 and poly-ADPribose polymerase was insignificantly affected in K562 cells following adenine treatment. In K562 cells, adenine was able to markedly promote the phosphorylation of AMPKα and suppress the phosphorylation of mammalian target of rapamycin (mTOR), a downstream target of AMPK. In addition, inhibiting AMPK phosphorylation using dorsomorphin restored mTOR phosphorylation, inhibited the accumulation of LC3 and significantly recovered the suppressed cell viability in response to adenine. Taken together, the present results demonstrated that adenine induced G 2 /M phase arrest and autophagic cell death, consequently suppressing the viability of K562 cells, which may attribute to the AMPK activation triggered by adenine. These findings provide evidence that adenine may be beneficial to chronic myelogenous leukemia therapy by suppressing excessive cell proliferation.

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“…Knowing that AMPK can induce autophagy in mTORC1‐independent pathways27, 28, 29 and that mTORC1 is a negative regulator of autophagy,29 the obtained data suggest a dissociative AMPK‐mTORC1 axis with AMPK sustaining autophagy in KG‐1 cells. In fact, the reports of Sujobert et al and Pezze et al also showed a direct induction of autophagy by AMPK even in the presence of mTORC1 activation 21, 53…”

Section: Discussionmentioning

confidence: 93%

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

Pereira

Teixeira

Sampaio‐Marques

et al. 2018

J Cellular Molecular Medi

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Acute myeloid leukaemia (AML) comprises a heterogeneous group of hematologic neoplasms characterized by diverse combinations of genetic, phenotypic and clinical features representing a major challenge for the development of targeted therapies. Metabolic reprogramming, mainly driven by deregulation of the nutrient‐sensing pathways as AMPK, mTOR and PI3K/AKT, has been associated with cancer cells, including AML cells, survival and proliferation. Nevertheless, the role of these metabolic adaptations on the AML pathogenesis is still controversial. In this work, the metabolic status and the respective metabolic networks operating in different AML cells (NB‐4, HL‐60 and KG‐1) and their impact on autophagy and survival was characterized. Data show that whereas KG‐1 cells exhibited preferential mitochondrial oxidative phosphorylation metabolism with constitutive co‐activation of AMPK and mTORC1 associated with increased autophagy, NB‐4 and HL‐60 cells displayed a dependent glycolytic profile mainly associated with AKT/mTORC1 activation and low autophagy flux. Inhibition of AKT is disclosed as a promising therapeutical target in some scenarios while inhibition of AMPK and mTORC1 has no major impact on KG‐1 cells’ survival. The results highlight an exclusive metabolic profile for each tested AML cells and its impact on determination of the anti‐leukaemia efficacy and on personalized combinatory therapy with conventional and targeted agents.

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Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia

Cited by 96 publications

References 51 publications

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer

Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling

Signalling mechanisms that regulate metabolic profile and autophagy of acute myeloid leukaemia cells

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