Targeting glycogen metabolism in bladder cancer

Lew, Carolyn R.; Guin, Sunny; Theodorescu, Dan

doi:10.1038/nrurol.2015.111

Cited by 64 publications

(56 citation statements)

References 101 publications

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“…Here, we show that the bi-directional signaling between cancer cells and stromal CAFs triggers a metabolic switch in the cancer cells, turning off glycogen synthesis and prompting glycogen utilization. Therefore, blocking glycogen mobilization in cancer cells with glycogen phosphorylase (Henke and Sparks, 2006; Rines et al, 2016; Ritterson Lew et al, 2015) or PGM1 inhibitors might be a therapeutic strategy for the reduction of tumor dissemination in abdominally metastasizing cancers (e.g. ovarian, gastric, pancreatic, and colon cancer) after optimal cytoreduction.…”

Section: Discussionmentioning

confidence: 99%

Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis

et al. 2019

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Successful metastasis requires the co-evolution of stromal and cancer cells. We used stable isotope labeling of amino acids in cell culture coupled with quantitative, label-free phosphoproteomics to study the bidirectional signaling in ovarian cancer cells and human-derived, cancer-associated fibroblasts (CAFs) after co-culture. In cancer cells, the interaction with CAFs supported glycogenolysis under normoxic conditions and induced phosphorylation and activation of phosphoglucomutase 1, an enzyme involved in glycogen metabolism. Glycogen was funneled into glycolysis, leading to increased proliferation, invasion, and metastasis of cancer cells co-cultured with human CAFs. Glycogen mobilization in cancer cells was dependent on p38α MAPK activation in CAFs. In vivo, deletion of p38α in CAFs and glycogen phosphorylase inhibition in cancer cells reduced metastasis, suggesting that glycogen is an energy source used by cancer cells to facilitate metastatic tumor growth.

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Section: Discussionmentioning

confidence: 99%

Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis

et al. 2019

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“…Altered cellular metabolism, as for other types of cancer, is an intrinsic hallmark of bladder cancer progression. 48 However, UBC metabolism has been described based on a homogeneous approach. In the present study, we used a cohort of 111 UBC tissue sections previously characterized for several metabolismrelated proteins according to the traditional homogeneous view.…”

Section: Discussionmentioning

confidence: 99%

Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness

et al. 2016

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Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance. However, the specific role of MCTs in the metabolic compartmentalization within bladder tumors, namely their preponderance on the tumor stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n = 111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells' compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance.

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“…The inhibition of Warburg effect deprives the generation of ATP, decreasing cancer cells growth and proliferation [10, 11]. Thus, Warburg effect has received substantial attention as a novel therapeutic target in cancers including lung cancer [12, 13], leukemia [14], breast cancer [15–18], pancreatic cancer [19, 20], colorectal cancer [21, 22], bladder cancer [23], and multiple myeloma [24, 25]. In multiple myeloma, dichloroacetate, which is an inhibitor of aerobic glycolysis, has been reported to increase myeloma cell sensitivity to bortezomib [24].…”

Section: Introductionmentioning

confidence: 99%

NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase

Xia

et al. 2017

J Hematol Oncol

110

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BackgroundAerobic glycolysis, a hallmark of cancer, is characterized by increased metabolism of glucose and production of lactate in normaxia. Recently, pyruvate kinase M2 (PKM2) has been identified as a key player for regulating aerobic glycolysis and promoting tumor cell proliferation and survival.MethodsTandem affinity purification followed up by mass spectrometry (TAP-MS) and co-immunoprecipitation (Co-IP) were used to study the interaction between NIMA (never in mitosis gene A)-related kinase 2 (NEK2) and heterogeneous nuclear ribonucleoproteins (hnRNP) A1/2. RNA immunoprecipitation (RIP) was performed to identify NEK2 binding to PKM pre-mRNA sequence. Chromatin-immunoprecipitation (ChIP)-PCR was performed to analyze a transcriptional regulation of NEK2 by c-Myc. Western blot and real-time PCR were executed to analyze the regulation of PKM2 by NEK2.ResultsNEK2 regulates the alternative splicing of PKM immature RNA in multiple myeloma cells by interacting with hnRNPA1/2. RIP shows that NEK2 binds to the intronic sequence flanking exon 9 of PKM pre-mRNA. Knockdown of NEK2 decreases the ratio of PKM2/PKM1 and also other aerobic glycolysis genes including GLUT4, HK2, ENO1, LDHA, and MCT4. Myeloma patients with high expression of NEK2 and PKM2 have lower event-free survival and overall survival. Our data indicate that NEK2 is transcriptionally regulated by c-Myc in myeloma cells. Ectopic expression of NEK2 partially rescues growth inhibition and cell death induced by silenced c-Myc.ConclusionsOur studies demonstrate that NEK2 promotes aerobic glycolysis through regulating splicing of PKM and increasing the PKM2/PKM1 ratio in myeloma cells which contributes to its oncogenic activity.

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Targeting glycogen metabolism in bladder cancer

Cited by 64 publications

References 101 publications

Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis

Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis

Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness

NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase

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