Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation

Wang, Jianbin; Erickson, Jon W.; Fuji, Reina N.; Ramachandran, Sekar; Gao, Peng; Dinavahi, Ramani; Wilson, Kristin; Ambrosio, A.L.B.; Dias, Sandra M.G.; Dang, Chi V.; Cerione, Richard A.

doi:10.1016/j.ccr.2010.10.011

Cited by 117 publications

(179 citation statements)

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“…Given that our data indicate that deficiency in Gln metabolism leads to increased ROS, we queried the role of glutaminolysis‐dependent anti‐oxidant capacity in maintaining PK activity in NPCs. In order to examine the contribution of GLS1 activity in sustaining PKM2 activity, we evaluated the effect of 968 and BPTES, potent and selective allosteric GLS1 inhibitors (Robinson et al , 2007; Wang et al , 2010). Inhibition of GLS1 with 2.5 μM 968 as well as 0.1 and 1 μM BPTES increased ROS (Figure 3F).…”

Section: Resultsmentioning

confidence: 99%

FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells

Yeo

Lyssiotis

Zhang

et al. 2013

EMBO J

134

120

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Forkhead Box O (FoxO) transcription factors act in adult stem cells to preserve their regenerative potential. Previously, we reported that FoxO maintains the longterm proliferative capacity of neural stem/progenitor cells (NPCs), and that this occurs, in part, through the maintenance of redox homeostasis. Herein, we demonstrate that among the FoxO3-regulated genes in NPCs are a host of enzymes in central carbon metabolism that act to combat reactive oxygen species (ROS) by directing the flow of glucose and glutamine carbon into defined metabolic pathways. Characterization of the metabolic circuit observed upon loss of FoxO3 revealed a drop in glutaminolysis and filling of the tricarboxylic acid (TCA) cycle. Additionally, we found that glucose uptake, glucose metabolism and oxidative pentose phosphate pathway activity were similarly repressed in the absence of FoxO3. Finally, we demonstrate that impaired glucose and glutamine metabolism compromises the proliferative potential of NPCs and that this is exacerbated following FoxO3 loss. Collectively, our findings show that a FoxO3-dependent metabolic programme supports redox balance and the neurogenic potential of NPCs.

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Section: Resultsmentioning

confidence: 99%

FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells

Yeo

Lyssiotis

Zhang

et al. 2013

EMBO J

134

120

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“…Further, it may serve as a biochemical basis for developing therapeutic strategies to preferentially kill cancer cells. The original observations by Warburg have had a profound influence on our understanding of cancer biology, clinical diagnosis and cancer treatment .…”

Section: Discussionmentioning

confidence: 99%

“…The Warburg effect itself involves high levels of aerobic glycolysis catalyzed by pivotal enzymes that are therapeutically accessible to small drug‐like inhibitors. These molecules may be directed to primary and metastatic tumors, and their effects may be monitored by metabolic imaging .…”

Section: Introductionmentioning

confidence: 99%

Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma

et al. 2012

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In previous studies, lactate dehydrogenase A (LDHA) was identified as one of the leading genes that promote the proliferative and tumorigenic potential of malignancies. However, less definitive evidence was reported in hepatocellular carcinoma (HCC) cells. Furthermore, the role of LDHA in promoting metastasis of HCC, and its possible mechanism, is not clear. In this study, RNA interference (RNAi) mediated by lentiviral vectors (which induce strong down-regulation of gene expression) was used to analyze the role of LDHA in tumor growth and metastasis in HCC. We performed transient and stable RNAi knockdowns of LDHA in HCCLM3 cells, a line that over-expresses LDHA and has a high metastatic potential. Our studies reveal that previously unidentified effects of LHDA may mediate tumor growth and metastasic effects in HCC. First, HCC cell lines over-express LDHA. Second, LDHA inhibition results in increased apoptosis via production of reactive oxygen species in HCCLM3 cells. Thus, LDHA knockdown resulted in significant reduction in metastatic potential in a xenograft mouse model. Furthermore, we found that FAK, MMP-2, VEGF and E-cadherin proteins contribute to inhibitory effects on metastasis in HCC cells. These studies have important implications for understanding the mechanisms by which LDHA promotes tumor growth and metastasis.

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“…Metabolically, increased glutamine (Gln) use is critical for various cancer types, as it replenishes the citrate cycle intermediates for ATP production and with the input of pyruvate being deficient as manifested by the high glycolytic metabolism of the Warburg effect. It is noteworthy that Rho GTPases and NF‐κB activate cellular glutaminase activity converting glutamine to glutamate, although its detailed mechanism still remains to be discovered (Wang et al, ). Modulation of metabolism by RhoA may be critical for tumorigenesis as RhoA mutations have also been discovered in several cancer tissues.…”

Section: Perspectivesmentioning

confidence: 99%

Regulation of RhoA GTPase and various transcription factors in the RhoA pathway

Kim

Islam

Cho

et al. 2018

Journal Cellular Physiology

106

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RhoA GTPase plays a variety of functions in regulation of cytoskeletal proteins, cellular morphology, and migration along with various proliferation and transcriptional activity in cells. RhoA activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and the guanine nucleotide dissociation factor (GDI). The RhoA-RhoGDI complex exists in the cytosol and the active GTP-bound form of RhoA is located to the membrane. GDI displacement factors (GDFs) including IκB kinase γ (IKKγ) dissociate the RhoA-GDI complex, allowing activation of RhoA through GEFs. In addition, modifications of Tyr42 phosphorylation and Cys16/20 oxidation in RhoA and Tyr156 phosphorylation and oxidation of RhoGDI promote the dissociation of the RhoA-RhoGDI complex. The expression of RhoA is regulated through transcriptional factors such as c-Myc, HIF-1α/2α, Stat 6, and NF-κB along with several reported microRNAs. As the role of RhoA in regulating actin-filament formation and myosin-actin interaction has been well described, in this review we focus on the transcriptional activity of RhoA and also the regulation of RhoA message itself. Of interest, in the cytosol, activated RhoA induces transcriptional changes through filamentous actin (F-actin)-dependent ("actin switch") or-independent means. RhoA regulates the activity of several transcription regulators such as serum response factor (SRF)/MAL, AP-1, NF-κB, YAP/TAZ, β-catenin, and hypoxia inducible factor (HIF)-1α. Interestingly, RhoA also itself is localized to the nucleus by an as-yet-undiscovered mechanism.

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Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation

Cited by 117 publications

References 0 publications

FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells

FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells

Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma

Regulation of RhoA GTPase and various transcription factors in the RhoA pathway

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