Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier

Bensard, Claire; Wisidagama, Dona R.; Olson, Kristofor A.; Berg, Jordan A.; Krah, Nathan M.; Schell, John C.; Nowinski, Sara M.; Fogarty, Sarah; Bott, Alex J.; Peng, Wei; Dove, Katja K.; Tanner, Jason M.; Panic, Vanja; Cluntun, Ahmad A.; Lettlová, Sandra; Earl, Christian S.; Namnath, David F.; Vázquez-Arreguín, Karina; Villanueva, Claudio J.; Tantin, Dean; Murtaugh, L. Charles; Evason, Kimberley; Ducker, Gregory S.; Thummel, Carl S.; Rutter, Jared

doi:10.1016/j.cmet.2019.11.002

Cited by 131 publications

(111 citation statements)

References 73 publications

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“…This initial event was associated with hyperactivation of the Wnt/β-catenin pathway and loss of function of the APC tumor suppressor. In this study, expression of both MPC1 and MPC2 was found to be decreased in adenomas in two different mouse models of colon cancer, the azoxymethane and dextran sodium sulfate (AOM-DSS) models, as well as a genetic model of heterozygous loss of Apc in intestinal stem cells (Apc Lrig1KO/+ Mpc1 Lrig1KO mice) [94]. Targeted deletion of MPC1 in adult LRIG1 + intestinal stem cells (Mpc1 Lrig1KO ) led to an increased tumor burden and a substantial increase in the incidence of macroscopic tumors in the AOM-DSS model.…”

Section: The Role Of Mpc In Stemnessmentioning

confidence: 88%

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The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

et al. 2020

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Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced in the cytosol, it is oxidized in the mitochondria where it fuels the citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into mitochondria is through the recently identified mitochondrial pyruvate carrier (MPC). In this review, we report the latest findings on the physiology of the MPC and we discuss how a dysfunctional MPC can lead to diverse pathologies, including neurodegenerative diseases, metabolic disorders, and cancer.

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Section: The Role Of Mpc In Stemnessmentioning

confidence: 88%

“…More recently, MPC was shown to be involved in the initiation of intestinal tumor formation in mice and Drosophila [94]. Sporadic colon tumors are believed to follow a typical progression pathway in which the initial tumorigenic event triggers intestinal stem-cell hyperplasia, leading to the formation of a benign adenoma.…”

Section: The Role Of Mpc In Stemnessmentioning

confidence: 99%

The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

et al. 2020

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“…Several crucial processes and signaling pathways have been identified by GO enrichment analysis, caffeine metabolism, metabolic pathways, and KEGG pathway analysis including oxidation-reduction and the xenobiotic metabolic process. Previous research demonstrated that the oxidation-reduction process and xenobiotic metabolic process play a crucial role in the development of CRC or colorectal cancer cells (Bensard et al, 2020;Han et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Prognostic implications of metabolism-associated gene signatures in colorectal cancer

Miao

Wang

et al. 2020

PeerJ

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Colorectal cancer (CRC) is one of the most common and deadly malignancies. Novel biomarkers for the diagnosis and prognosis of this disease must be identified. Besides, metabolism plays an essential role in the occurrence and development of CRC. This article aims to identify some critical prognosis-related metabolic genes (PRMGs) and construct a prognosis model of CRC patients for clinical use. We obtained the expression profiles of CRC from The Cancer Genome Atlas database (TCGA), then identified differentially expressed PRMGs by R and Perl software. Hub genes were filtered out by univariate Cox analysis and least absolute shrinkage and selection operator Cox analysis. We used functional enrichment analysis methods, such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis, to identify involved signaling pathways of PRMGs. The nomogram predicted overall survival (OS). Calibration traces were used to evaluate the consistency between the actual and the predicted survival rate. Finally, a prognostic model was constructed based on six metabolic genes (NAT2, XDH, GPX3, AKR1C4, SPHK1, and ADCY5), and the risk score was an independent prognostic prognosticator. Genetic expression and risk score were significantly correlated with clinicopathologic characteristics of CRC. A nomogram based on the clinicopathological feature of CRC and risk score accurately predicted the OS of individual CRC cancer patients. We also validated the results in the independent colorectal cancer cohorts GSE39582 and GSE87211. Our study demonstrates that the risk score is an independent prognostic biomarker and is closely correlated with the malignant clinicopathological characteristics of CRC patients. We also determined some metabolic genes associated with the survival and clinical stage of CRC as potential biomarkers for CRC diagnosis and treatment.

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“…Several studies have indicated that multiple cancers exhibited diminished MPC expression and activity, which causing dysfunction of mitochondrial pyruvate uptake. High glycolysis of tumor cells is known as the Warburg effect and the MPC is likely involved in the Warburg effect, which offers a potential target for cancer therapy [29][30][31]. Growing evidence supported that the altered mitochondrial function and the Warburg effect were closely correlated in the development of DN [32].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial pyruvate carrier: a potential target for diabetic nephropathy

Zhu

Wan

et al. 2020

BMC Nephrol

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Background: Mitochondrial dysfunction contributes to the pathogenesis of diabetic nephropathy (DN). Mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2) play a bottleneck role in the transport of pyruvate into mitochondrial across the mitochondrial inner membrane. A previous study showed that increasing mitochondrial pyruvate carrier content might ameliorate diabetic kidney disease in db/db mice. However, the expression status of MPC1 and MPC2 in patients with DN is unclear. Methods: Patients with primary glomerulonephropathy (PGN, n = 30), PGN with diabetes mellitus (PGN-DM, n = 30) and diabetic nephropathy (DN, n = 30) were included. MPC1 and MPC2 protein levels were examined by immunohistochemistry. The expression of MPC in different groups was evaluated by the Kruskal-Wallis test. Spearman's rank correlation was performed for correlation analysis between MPC levels and clinical factors. Results: Both MPC1 and MPC2 were localized in renal tubules. Levels of MPC1 and MPC2 were lower in DN patients than in PGN patients and in PGN patients with DM, whereas there were no differences in MPC1 and MPC2 levels among DN stage II to stage IV. Moreover, both MPC1 and MPC2 levels were significantly correlated with serum creatinine, BUN and eGFR in patients with DN, whereas no analogous trend was observed in nondiabetic kidney disease. Conclusions: Our study indicated that MPC localized in renal tubules, which were significantly decreased in DN. MPC was associated with clinical features, especially those representing renal functions.

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Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier

Cited by 131 publications

References 73 publications

The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

Prognostic implications of metabolism-associated gene signatures in colorectal cancer

Mitochondrial pyruvate carrier: a potential target for diabetic nephropathy

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