Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo

Courtney, Kevin D.; Bezwada, Divya; Mashimo, Tomoyuki; Pichumani, Kumar; Vemireddy, Vamsidhara; Funk, Alexander; Wimberly, Jennifer; McNeil, Sarah S.; Kapur, Payal; Lotan, Yair; Margulis, Vitaly; Cadeddu, Jeffrey A.; Pedrosa, Iván; DeBerardinis, Ralph J.; Malloy, Craig R.; Bachoo, Robert; Maher, Elizabeth A.

doi:10.1016/j.cmet.2018.07.020

Cited by 228 publications

(276 citation statements)

References 35 publications

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“…Recent isotope tracing analysis of human ccRCC confirmed enhanced glycolysis and suppressed glucose oxidation by the TCA cycle in these tumors (Courtney et al, 2018), likely due to HIF stabilization caused by frequent von Hippel-Lindau (VHL) mutations (Nickerson et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

Huangyang

Lee

et al. 2020

Cell Metabolism

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Sarcomas are uncommon but diverse mesenchymal malignancies arising from connective tissues, such as muscle, fat and cartilage. Despite rapid advances in molecular understanding of individual subtypes and pathway-specific therapies, the remarkable cellular and genetic heterogeneity of soft tissue sarcomas (STS) limits clinical benefit of targeted treatments. A variety of metabolism-associated oncogenic signaling pathways have been identified in sarcomas. Both these internal and external alterations converge to change cell metabolism, rendering sarcoma cells more susceptible to perturbations within metabolic networks. However, how abnormal metabolism influences sarcoma growth remains understudied. I show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of STS subtypes, revealing an apparent common metabolic feature shared by diverse STS. Enforced FBP2 re-expression inhibits STS cell and tumor growth through two distinct mechanisms. First, cytosolic FBP2 antagonizes elevated glycolysis associated with the "Warburg effect", thereby inhibiting sarcoma cell proliferation. Second, nuclear-localized FBP2 restrains mitochondrial biogenesis and respiration in a catalytic activity-independent manner by inhibiting the expression of nuclear respiratory factor (NRF1) and mitochondrial transcription factor A (TFAM). Specifically, nuclear FBP2 colocalizes with the c-Myc transcription factor at the TFAM locus and represses c-Myc-dependent TFAM expression. This unique dual function of FBP2 provides a rationale for its selective suppression in STS, identifying a potential metabolic vulnerability and possible future therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

Huangyang

Lee

et al. 2020

Cell Metabolism

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“…33,34 For example, we observed higher abundance of glucose and lactate, attributable to the upregulation of glucose transporter 1 35 and lactate dehydrogenase associated with a shift toward aerobic glycolysis. 36,37 Succinate and fumarate, members of the TCA cycle decrease with this metabolism shift, while glutamate increase, coinciding with induction of glutaminolysis. 34 Alterations in glutamine and more generally amino acid metabolism are indeed reflected by the statistical models, which select for N-acetyl aspartic acid, and N-acetyl glutamate peaks in the classification.…”

Section: Discussionmentioning

confidence: 99%

Identification of diagnostic metabolic signatures in clear cell renal cell carcinoma using mass spectrometry imaging

Vijayalakshmi

Shankar

Bain

et al. 2020

Intl Journal of Cancer

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Clear cell renal cell carcinoma (ccRCC) is the most common and lethal subtype of kidney cancer. Intraoperative frozen section (IFS) analysis is used to confirm the diagnosis during partial nephrectomy. However, surgical margin evaluation using IFS analysis is time consuming and unreliable, leading to relatively low utilization. In our study, we demonstrated the use of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) as a molecular diagnostic and prognostic tool for ccRCC. DESI-MSI was conducted on fresh-frozen 23 normal tumor paired nephrectomy specimens of ccRCC. An independent validation cohort of 17 normal tumor pairs was analyzed. DESI-MSI provides two-dimensional molecular images of tissues with mass spectra representing small metabolites, fatty acids and lipids. These tissues were subjected to histopathologic evaluation. A set of metabolites that distinguish ccRCC from normal kidney were identified by performing least absolute shrinkage and selection operator (Lasso) and log-ratio Lasso analysis. Lasso analysis with leave-one-patient-out crossvalidation selected 57 peaks from over 27,000 metabolic features across 37,608 pixels obtained using DESI-MSI of ccRCC and normal tissues. Baseline Lasso of metabolites predicted the class of each tissue to be normal or cancerous tissue with an accuracy of 94 and 76%, respectively. Combining the baseline Lasso with the ratio of glucose to arachidonic acid could potentially reduce scan time and improve accuracy to identify normal (82%) and ccRCC (88%) tissue. DESI-MSI allows rapid detection of metabolites associated with normal and ccRCC with high accuracy. As this technology advances, it could be used for rapid intraoperative assessment of surgical margin status.K.V.L. and V.S. contributed equally to this work Ryan M. Bain's current address is: Dow Chemical Co., Midland, MI 48674 Additional Supporting Information may be found in the online version of this article.

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“…PDH plays a crucial regulatory role by tuning glycolytic metabolism in cancer cells . Enhanced glycolysis inhibited pyruvate dehydrogenase flow, and downregulated TCA cycle labeling, consistent with the Warburg effect . Furthermore, several studies reported that SIRT3 expression may be correlated with hexokinase‐1 (HK1) and hexokinase‐2 (HK2) expression in the regulation of glucose metabolism in ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis

Yang

Zhou

et al. 2019

Cancer Medicine

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Cholangiocarcinoma (CCA) is an extremely invasive malignancy with late diagnosis and unfavorable prognosis. Surgery and chemotherapy are still not effective in improving outcomes in CCA patients. It is crucial to explore a novel therapeutic target for treating CCA. An NAD‐dependent deacetylase also known as Sirtuin‐3 (SIRT3) has been shown to regulate cellular metabolism in various cancers dynamically. However, the biological function of SIRT3 in CCA remains unclear. In this study, bioinformatics analyses were performed to identify the differentially expressed genes and pathways enriched. CCA samples were collected for immunohistochemical analysis. Three human CCA cell lines (HuCCT1, RBE, and HCCC9810) were used to explore the molecular mechanism of SIRT3 regulation of metabolic reprogramming and malignant behavior in CCA. A CCA xenograft model was then established for further validation in vivo. The data showed that SIRT3 expression was decreased and glycolysis was enhanced in CCA. Similar metabolic reprogramming was also observed in SIRT3 knockout mice. Furthermore, we demonstrated that SIRT3 could play an anti‐Warburg effect by inhibiting the hypoxia‐inducible factor‐1α (HIF1α)/pyruvate dehydrogenase kinase 1 (PDK1)/pyruvate dehydrogenase (PDHA1) pathway in CCA cells. CCA cell proliferation and apoptosis were regulated by SIRT3‐mediated metabolic reprogramming. These findings were further confirmed in CCA clinical samples and the xenograft model. Collectively, this study suggests that in the inhibition of CCA progression, SIRT3 acts through an anti‐Warburg effect on the downstream pathway HIF1α/PDK1/PDHA1.

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Isotope Tracing of Human Clear Cell Renal Cell Carcinomas Demonstrates Suppressed Glucose Oxidation In Vivo

Cited by 228 publications

References 35 publications

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

Identification of diagnostic metabolic signatures in clear cell renal cell carcinoma using mass spectrometry imaging

SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis

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