Bioenergetic properties of human sarcoma cells help define sensitivity to metabolic inhibitors

Issaq, Sameer H.; Teicher, Beverly A.; Monks, Anne

doi:10.4161/cc.28010

Cited by 41 publications

(41 citation statements)

References 23 publications

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“…This disparity in part results from the inability of MyoD to properly bind to and activate its target myogenic genes (MacQuarrie et al, 2013). Interestingly, a study examining the metabolic properties of human rhabdomyosarcoma tumors revealed a dependence on glycolysis reminiscent of the Warburg effect (Issaq et al, 2014). Given our current results, it is intriguing to posit that loss of MyoD function not only compromises the differentiation status of rhabdomyosarcoma tumor cells, but in addition contributes to the metabolic shift through the decline of PGC-1β and potentially other regulators of oxidative metabolism.…”

Section: Discussionmentioning

confidence: 99%

MyoD Regulates Skeletal Muscle Oxidative Metabolism Cooperatively with Alternative NF-κB

et al. 2016

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SUMMARY MyoD is a key regulator of skeletal myogenesis that directs contractile protein synthesis, but whether this transcription factor also regulates skeletal muscle metabolism has not been explored. In a genome-wide ChIP-seq analysis of skeletal muscle cells, we unexpectedly observed that MyoD directly binds to numerous metabolic genes, including those associated with mitochondrial biogenesis, fatty acid oxidation, and the electron transport chain. Results in cultured cells and adult skeletal muscle confirmed that MyoD regulates oxidative metabolism through multiple transcriptional targets including PGC-1β, a master regulator of mitochondrial biogenesis. We find that PGC-1β expression is cooperatively regulated by MyoD and the alternative NF-κB signaling pathway. Bioinformatics evidence suggests that this cooperativity between MyoD and NF-κB extends to other metabolic genes as well. Together, these data identify MyoD as a regulator of the metabolic capacity of mature skeletal muscle to ensure that sufficient energy is available to support muscle contraction.

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Section: Discussionmentioning

confidence: 99%

MyoD Regulates Skeletal Muscle Oxidative Metabolism Cooperatively with Alternative NF-κB

et al. 2016

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“…Oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) of HT-29 colon cancer cells were measured in real time using a Seahorse Bioscience XF24 Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA, USA) as described [31–35]. To achieve ~85% confluence, the optimum number of cells/well was determined in preliminary studies.…”

Section: Methodsmentioning

confidence: 99%

Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases

Risbood

Kane

et al. 2017

Biochemical Pharmacology

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The NADPH oxidases (NOXs) play a recognized role in the development and progression of inflammation-associated disorders, as well as cancer. To date, several NOX inhibitors have been developed, through either high throughput screening or targeted disruption of NOX interaction partners, although only a few have reached clinical trials. To improve the efficacy and bioavailability of the iodonium class NOX inhibitor diphenylene iodonium (DPI), we synthesized 36 analogs of DPI, focusing on improved solubility and functionalization. The inhibitory activity of the analogs was interrogated through cell viability and clonogenic studies with a colon cancer cell line (HT-29) that depends on NOX for its proliferative potential. Lack of altered cellular respiration at relevant iodonium analog concentrations was also demonstrated. Additionally, inhibition of ROS generation was evaluated with a luminescence assay for superoxide, or by Amplex Red® assay for H2O2 production, in cell models expressing specific NOX isoforms. DPI and four analogs (NSCs 740104, 751140, 734428, 737392) strongly inhibited HT-29 cell growth and ROS production with nanomolar potency in a concentration-dependent manner. NSC 737392 and 734428, which both feature nitro functional groups at the meta position, had >10-fold higher activity against ROS production by cells that overexpress dual oxidase 2 (DUOX2) than the other compounds examined (IC50 ≈ 200–400 nM). Based on these results, we synthesized and tested NSC 780521 with optimized potency against DUOX2. Iodonium analogs with anticancer activity, including the first generation of targeted agents with improved specificity against DUOX2, may provide a novel therapeutic approach to NOX-driven tumors.

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“…An enhanced antioxidant capacity allows cancer cells to not a universal finding, and mitochondrial respiration impairment is not a fixed feature of cancer cells [41] . Although the glycolytic inhibitors targeting the Warburg effect have been investigated in various cancer types, the glycolytic inhibitors with the exception of 3-BP (a lactate analog) [18,19, , 3-BrOP (a 3-bromopyruvate derivative) [71][72][73][74] , and dichloroacetate (DCA) have demonstrated low efficacy in arresting tumor growth when used alone [99] ; these inhibitors include 2-deoxy-D-glucose (a glucose analog) [70,[100][101][102][103][104][105][106][107][108][109][110][111][112] , lonidamine (a derivative of indazole-3-carboxylic acid) [113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] , methyl jasmonate on HK , 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one on PFK [162]…”

Section: Initiation Of Metastasismentioning

confidence: 99%

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

Lee¹

2015

WJBC

124

115

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Aerobic glycolysis, i.e. , the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e. , the "reverse Warburg effect". Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.

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Bioenergetic properties of human sarcoma cells help define sensitivity to metabolic inhibitors

Cited by 41 publications

References 23 publications

MyoD Regulates Skeletal Muscle Oxidative Metabolism Cooperatively with Alternative NF-κB

MyoD Regulates Skeletal Muscle Oxidative Metabolism Cooperatively with Alternative NF-κB

Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

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