ATP Depletion Triggers Acute Myeloid Leukemia Differentiation through an ATR/Chk1 Protein-dependent and p53 Protein-independent Pathway

Sharma, James Prabhakar; Yang, Jinbo; Agarwal, Anju; Glick, Abigail; Zhang, Youwei; Agarwal, Munna L.; Agarwal, Megha; Wald, David N.

doi:10.1074/jbc.m111.312801

Cited by 11 publications

(8 citation statements)

References 23 publications

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“…Decreased ATP, AMPK activation and myeloid differentiation were again noted, but Myc levels were unaffected. These studies supported the idea that ATP levels are a strong and Myc-independent determinant of differentiation, at least in myeloid cells ( 193 ). They further implied that a major role of Myc in differentiation is to maintain ATP levels, most likely with the purpose of allowing for the continued accumulation of biomass.…”

Section: Myc and The Regulation Of Glycolysis Oxphos And Energy Balsupporting

confidence: 81%

The Role for Myc in Coordinating Glycolysis, Oxidative Phosphorylation, Glutaminolysis, and Fatty Acid Metabolism in Normal and Neoplastic Tissues

2018

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That cancer cells show patterns of metabolism different from normal cells has been known for over 50 years. Yet, it is only in the past decade or so that an appreciation of the benefits of these changes has begun to emerge. Altered cancer cell metabolism was initially attributed to defective mitochondria. However, we now realize that most cancers do not have mitochondrial mutations and that normal cells can transiently adopt cancer-like metabolism during periods of rapid proliferation. Indeed, an encompassing, albeit somewhat simplified, conceptual framework to explain both normal and cancer cell metabolism rests on several simple premises. First, the metabolic pathways used by cancer cells and their normal counterparts are the same. Second, normal quiescent cells use their metabolic pathways and the energy they generate largely to maintain cellular health and organelle turnover and, in some cases, to provide secreted products necessary for the survival of the intact organism. By contrast, undifferentiated cancer cells minimize the latter functions and devote their energy to producing the anabolic substrates necessary to maintain high rates of unremitting cellular proliferation. Third, as a result of the uncontrolled proliferation of cancer cells, a larger fraction of the metabolic intermediates normally used by quiescent cells purely as a source of energy are instead channeled into competing proliferation-focused and energy-consuming anabolic pathways. Fourth, cancer cell clones with the most plastic and rapidly adaptable metabolism will eventually outcompete their less well-adapted brethren during tumor progression and evolution. This attribute becomes increasingly important as tumors grow and as their individual cells compete in a constantly changing and inimical environment marked by nutrient, oxygen, and growth factor deficits. Here, we review some of the metabolic pathways whose importance has gained center stage for tumor growth, particularly those under the control of the c-Myc (Myc) oncoprotein. We discuss how these pathways differ functionally between quiescent and proliferating normal cells, how they are kidnapped and corrupted during the course of transformation, and consider potential therapeutic strategies that take advantage of common features of neoplastic and metabolic disorders.

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Section: Myc and The Regulation Of Glycolysis Oxphos And Energy Balsupporting

confidence: 81%

The Role for Myc in Coordinating Glycolysis, Oxidative Phosphorylation, Glutaminolysis, and Fatty Acid Metabolism in Normal and Neoplastic Tissues

2018

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“…Adenosine analogues have been proposed as a possible differentiation-inducing agent against AML in B4 cells [497]. ATP depletion triggers AML differentiation (and is therefore anti-proliferative) through an ATR/Chk1 protein-dependent and a p53 protein-independent pathway and therefore is a promising strategy for treatment of AML [498]. AML cells express P2X1, P2X4, P2X5 and P2X7 and all P2Y receptor subtypes [499].…”

Section: Myeloid (Myelogenous) Leukaemiamentioning

confidence: 99%

Purinergic signalling and cancer

Burnstock

Virgilio

2013

Purinergic Signalling

272

265

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Receptors for extracellular nucleotides are widely expressed by mammalian cells. They mediate a large array of responses ranging from growth stimulation to apoptosis, from chemotaxis to cell differentiation and from nociception to cytokine release, as well as neurotransmission. Pharma industry is involved in the development and clinical testing of drugs selectively targeting the different P1 nucleoside and P2 nucleotide receptor subtypes. As described in detail in the present review, P2 receptors are expressed by all tumours, in some cases to a very high level. Activation or inhibition of selected P2 receptor subtypes brings about cancer cell death or growth inhibition. The field has been largely neglected by current research in oncology, yet the evidence presented in this review, most of which is based on in vitro studies, although with a limited amount from in vivo experiments and human studies, warrants further efforts to explore the therapeutic potential of purinoceptor targeting in cancer.

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“…Cells were pre-incubated with broadly active Phosphoinositide 3-kinase (PI3K) inhibitors wortmannin, caffeine and LY294002 before S009-131 treatment and level of p-p53 (Ser 15) was monitored by immunoblotting. While ATM and DNA-PK are more sensitive to wortmannin2425, caffeine has relative specificity towards ATM and ATR25. On the other hand, LY294002 is comparatively more potent inhibitor of DNA-PK26.…”

Section: Resultsmentioning

confidence: 99%

Coumarin-chalcone hybrid instigates DNA damage by minor groove binding and stabilizes p53 through post translational modifications

Ashraf

Ullah

Hasanain

et al. 2017

Sci Rep

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S009-131, a coumarin-chalcone hybrid, had been shown to possess anti-proliferative and anti-tumour effect by triggering apoptosis. In this report, we investigated role of DNA damage signalling pathway in S009-131 induced cancer cell death. Here we show that S009-131 causes DNA damage by potential binding to the minor groove which led to the phosphorylation and activation of ATM and DNA-PK, but not ATR, at earlier time points in order to initiate repair process. S009-131 induced DNA damage response triggered activation of p53 through phosphorylation at its key residues. Pharmacological inhibition of PIKKs abrogated S009-131 induced phosphorylation of p53 at Ser 15. DNA damage induced phosphorylation resulted in reduced proteasomal degradation of p53 by disrupting p53-MDM2 interaction. Additionally, our docking studies revealed that S009-131 might also contribute to increased cellular p53 level by occupying p53 binding pocket of MDM2. Posttranslational modifications of p53 upon S009-131 treatment led to enhanced affinity of p53 towards responsive elements (p53-RE) in the promoter regions of target genes and increased transcriptional efficiency. Together, the results suggest that S009-131 cleaves DNA through minor groove binding and eventually activates PIKKs associated DNA damage response signalling to promote stabilization and enhanced transcriptional activity of p53 through posttranslational modifications at key residues.

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ATP Depletion Triggers Acute Myeloid Leukemia Differentiation through an ATR/Chk1 Protein-dependent and p53 Protein-independent Pathway

Cited by 11 publications

References 23 publications

The Role for Myc in Coordinating Glycolysis, Oxidative Phosphorylation, Glutaminolysis, and Fatty Acid Metabolism in Normal and Neoplastic Tissues

The Role for Myc in Coordinating Glycolysis, Oxidative Phosphorylation, Glutaminolysis, and Fatty Acid Metabolism in Normal and Neoplastic Tissues

Purinergic signalling and cancer

Coumarin-chalcone hybrid instigates DNA damage by minor groove binding and stabilizes p53 through post translational modifications

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