Glycogen metabolism in humans

Edited by Ruma BanerjeeHypoxia and dysregulated metabolism are defining features of solid tumors. How cancer cells adapt to low O 2 has been illuminated by numerous studies, with "reprogrammed" metabolism being one of the most important mechanisms. This metabolic reprogramming not only promotes cancer cell plasticity, but also provides novel insights for treatment strategies. As the most studied O 2 "sensor," hypoxia-inducible factor (HIF) is regarded as an important regulator of hypoxia-induced transcriptional responses. This minireview will summarize our current understanding of hypoxia-induced changes in cancer cell metabolism, with an initial focus on HIF-mediated effects, and will highlight how these metabolic alterations affect malignant phenotypes.Molecular oxygen (O 2 ) is a key nutrient required for aerobic metabolism to maintain intracellular bioenergetics and as a substrate in numerous organic and inorganic reactions. Hypoxia, defined by a deficiency in the amount of tissue O 2 levels, occurs in a variety of physiological as well as pathological conditions. Significant research interest in variable O 2 availability in cancers can be traced to the early 20th century, when Otto Warburg found that unlike most normal tissues, cancer cells preferentially "ferment" glucose to pyruvate and then lactate even in the presence of sufficient O 2 to support mitochondrial metabolism (the "Warburg effect"). Although the underlying mechanisms of this observation were not clear and numerous subsequent studies demonstrated certain limitations in this theory (especially the hypothesis that cancer cells develop a defect in mitochondria that leads to impaired aerobic respiration), it opened a new territory of investigating how cancer cells rewire metabolism to adapt to changes in O 2 levels. When facing hypoxia, cells modulate a number of conserved molecular responses, including those regulated by hypoxiainducible factors (HIFs), 3 endoplasmic reticulum (ER) stress responses, mechanistic target of rapamycin signaling, autophagy, and others. These processes promote altered metabolism to match O 2 supply. In this minireview, we will discuss hypoxia responses according to HIF-dependent and -independent pathways and how they impact progression of solid tumors. HIF-dependent metabolic reprogrammingThe HIF hydroxylase systemThe HIF system itself has been reviewed extensively elsewhere (1, 2). Initially identified as a transcriptional regulator bound to a hypoxia-response element (HRE) of the erythropoietin (EPO) gene to promote EPO production, it readily became apparent that this pathway operated much more widely, and it is currently recognized as a key modulator of the transcriptional response to hypoxic stress. Briefly, HIFs are heterodimeric transcription factors consisting of ␣ and ␤ subunits. Three HIF␣ isoforms exist in the mammalian genome (1␣, 2␣, and 3␣), of which HIF1␣ and HIF2␣ are the best characterized. HIF␣ subunits heterodimerize with stable HIF1␤ (or ARNT), recognize, and then bind to HREs ((G/A)CGTG) throughout...

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“…1A) (11). Glycogen accumulation has been described in various cancer cells, although its abundance varies greatly across tumor types (12).…”

Section: Minireview: O 2 Availability and Metabolism In Cancermentioning

confidence: 99%

Oxygen availability and metabolic reprogramming in cancer

Xie

Simon

2017

Journal of Biological Chemistry

155

130

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“…AGL, or glycogen debranching enzyme, is involved in glycogen breakdown (glycogenolysis) (10). Germline mutations identified in AGL have been associated with Cori disease, otherwise known as glycogen storage disease III (GSD III), characterized by irregular glycogenolysis and accumulation of abnormally branched glycogen (limit dextrin) in the liver (10,11).…”

Section: Identification Of Glycogen Debranching Enzyme (Agl) As a Newmentioning

confidence: 99%

“…Germline mutations identified in AGL have been associated with Cori disease, otherwise known as glycogen storage disease III (GSD III), characterized by irregular glycogenolysis and accumulation of abnormally branched glycogen (limit dextrin) in the liver (10,11). The symptomatic diagnosis of GSD III…”

Section: Identification Of Glycogen Debranching Enzyme (Agl) As a Newmentioning

confidence: 99%

“…Further analysis of AGL low tumor cells presented increased production of limit dextrin, or abnormally branched glycogen, similar to patients with GSD III. To understand in detail whether a connection between inhibition of glycogen breakdown and aggressive bladder cancer growth existed, the authors investigated the role of glycogen phosphorylase (PYG), the other enzyme known to interplay with AGL in glycogen breakdown (9,10,12). In addition, experiments using enzymatic null mutants of AGL were conducted to understand AGL's enzymatic activity in bladder tumor growth (9).…”

Section: Agl Glycogen Metabolism and Regulation Of Glycine Synthesismentioning

confidence: 99%

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Involvement of glycogen debranching enzyme in bladder cancer

Weinhaus

Guin

2017

Biomedical Reports

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Abstract. Bladder cancer is the most common malignancy of the urinary system, however the molecular pathways underlying this disease are incompletely understood. To understand new regulators of bladder cancer progression, the authors carried out a functional genomic screen which identified glycogen debranching enzyme (AGL) as a novel regulator of bladder cancer growth. Glycogen debranching enzyme is involved in glycogen breakdown and germline loss of function mutation of this gene leads to glycogen storage disease type III. To the best of the authors' knowledge, the present study is the first to demonstrate that loss of AGL leads to aggressive bladder tumor growth. AGL mRNA and protein expression in bladder tumors serve as a prognostic marker for patients. Interestingly, AGL's participation in regulating tumor growth is independent of its enzymatic function and involvement with glycogen metabolism in general. Detailed metabolomics and transcriptomic analysis indicated that increases in glucose metabolism, glycine synthesis driven by serine hydroxymethyltransferase 2 and increases in hyaluronic acid synthase 2-driven HA synthesis are major contributors of aggressive bladder tumor growth with loss of AGL. However, the detailed mechanism of how AGL regulates the above mentioned metabolic and genetic pathways is unknown and is being investigated. The present review focuses on AGL's involvement in bladder cancer.

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“…The treatment of choice is surgery [12], but there is lack of consensus about the extent of the surgical approach (i.e., conservative wide local excision versus radical surgery) and the role of the sentinel node biopsy for microscopic staging. The benefıt of adjuvant therapies for higher-risk (i.e., American Joint Committee on Cancer (AJCC) stage II or III) melanomas after surgical excision needs to be further investigated [13,14]. Due to the rarity of these tumors and the lack of evidence-based guidelines for the management of vulvar and vaginal melanoma, these patients are usually treated in accordance to principles of management of cutaneous melanoma [14][15][16].…”

mentioning

confidence: 99%

Molecular profiling and clinico-pathological characteristics of vulvar and vaginal melanomas

Fumagalli¹,

Tosti²,

Gandini³

et al. 2016

J Transl Sci

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Vulvar and vaginal melanomas are infrequent malignancies characterized by an aggressive behaviour and a poor prognosis. Surgery is the treatment of choice for primary tumors and loco-regional metastases. As target therapies have emerged as effective treatments both in the advanced and adjuvant settings, molecular profiling of primary tumors and/or metastases is mandatory in order to choose the proper treatment in melanoma patients harbouring specific mutations. Recently, some studies have analyzed the molecular profile of urogenital melanomas, but limited to few specimens and ending with a lack of general agreement. We evaluated a cohort of vulvar and vaginal melanomas for clinical-pathological parameters and molecular profile of the most frequently mutated genes in melanomas, KIT, BRAF and NRAS. Our study population was composed of 23 cases, including 14 vulvar, 7 vaginal and 2 cases of concomitant vulvar and vaginal melanomas. We analyzed clinical-pathological parameters such as histotype, number of mitoses, presence of ulceration, regression, vascular invasion and metastasis, in addition to recurrence and overall survival. Molecular analyses were performed by bi-directional Sanger sequencing for KIT (exons 9, 11, 13 and 17), BRAF (exons 11 and 15) and NRAS (exons 2 and 3). We applied multivariate models to assess the associations of KIT, BRAF and NRAS status with prognostic factors, adjusting for age. KIT mutations were found in 4 samples (17%), 3 vulvar and 1 vaginal melanoma. NRAS alterations were observed in 2 of 15 available samples (13%) equally distributed between the two categories; BRAF mutations were detected in 1 vulvar melanoma of 19 available samples (5%). KIT mutation was associated with significantly lower number of mitosis and lower Breslow thickness (P=0.01 and P=0.05, respectively, adjusting for age and site). Thicker melanomas were found to be associated with a worse progression free and overall survival (P=0.01 and P=0.03, respectively, adjusting for age). In conclusion in our cohort, melanomas of female genital tract harboured mutations in all the three genes tested, with KIT and NRAS most commonly mutated. KIT status was found to be significantly associated with prognostic factors. Since melanoma patients carrying mutations of KIT, NRAS or BRAF might benefit from target therapy such as imatinib, MEK inhibitor or anti-BRAF drugs, we suggest that even in these rare melanomas molecular analysis should be performed in order to drive proper therapeutic treatment. IntrodutionVaginal and vulvar melanomas are rare tumors, representing 1-3% of melanomas arise in women [1,2] and less than 1% of all female genital tract malignancies [3,4]. Among primary melanomas of the genital tract, vulvar melanomas exhibit the highest frequency, followed by vaginal and cervical. The estimated incidence is 0.1-0.2/100.000 and 0.26-0.46/1.000.000 new diagnosed cases per year of vulvar and vaginal melanomas, respectively [1,2,5,6]. Primary vulvar and vaginal melanomas more frequently occur in Caucasian women...

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Glycogen metabolism in humans

Cited by 372 publications

References 134 publications

Oxygen availability and metabolic reprogramming in cancer

Oxygen availability and metabolic reprogramming in cancer

Involvement of glycogen debranching enzyme in bladder cancer

Molecular profiling and clinico-pathological characteristics of vulvar and vaginal melanomas

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