Metabolic phenotype of bladder cancer

Francesco Massari, Chiara Ciccarese, Matteo Santoni, Roberto Iacovelli, Roberta Mazzucchelli, Francesco Piva, Marina Scarpelli, Rossana Berardi, Giampaolo Tortora, Antonio Lopez-Beltran, Liang Cheng, Rodolfo Montironi

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Metabolism of bladder cancer represents a key issue for cancer research. Several metabolic altered pathways are involved in bladder tumorigenesis, representing therefore interesting targets for therapy. Tumor cells, including urothelial cancer cells, rely on a peculiar shift to aerobic glycolysis-dependent metabolism (the Warburg-effect) as the main energy source to sustain their uncontrolled growth and proliferation. Therefore, the high glycolytic flux depends on the overexpression of glycolysis-related genes (SRC-3, glucose transporter type 1 [GLUT1], GLUT3, lactic dehydrogenase A [LDHA], LDHB, hexokinase 1 [HK1], HK2, pyruvate kinase type M [PKM], and hypoxia-inducible factor 1-alpha [HIF-1α]), resulting in an overproduction of pyruvate, alanine and lactate. Concurrently, bladder cancer metabolism displays an increased expression of genes favoring the pentose phosphate pathway (glucose-6-phosphate dehydrogenase [G6PD]) and the fatty-acid synthesis (fatty acid synthase [FASN]), along with a decrease of AMP-activated protein kinase (AMPK) and Krebs cycle activities. Moreover, the PTEN/PI3K/AKT/mTOR pathway, hyper-activated in bladder cancer, acts as central regulator of aerobic glycolysis, hence contributing to cancer metabolic switch and tumor cell proliferation. Besides glycolysis, glycogen metabolism pathway plays a robust role in bladder cancer development. In particular, the overexpression of GLUT-1, the loss of the tumor suppressor glycogen debranching enzyme amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL), and the increased activity of the tumor promoter enzyme glycogen phosphorylase impair glycogen metabolism. An increase in glucose uptake, decrease in normal cellular glycogen storage, and overproduction of lactate are consequences of decreased oxidative phosphorylation and inability to reuse glucose into the pentose phosphate and de novo fatty acid synthesis pathways. Moreover, AGL loss determines augmented levels of the serine-to-glycine enzyme serine hydroxymethyltransferase-2 (SHMT2), resulting in an increased glycine and purine ring of nucleotides synthesis, thus supporting cells proliferation. A deep understanding of the metabolic phenotype of bladder cancer will provide novel opportunities for targeted therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)46-57
Number of pages12
JournalCancer Treatment Reviews
Volume45
DOIs
StatePublished - Apr 1 2016

Keywords

  • Bladder cancer
  • Metabolic pathway
  • Metabolism
  • Novel target

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

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    Massari, F., Ciccarese, C., Santoni, M., Iacovelli, R., Mazzucchelli, R., Piva, F., Scarpelli, M., Berardi, R., Tortora, G., Lopez-Beltran, A., Cheng, L., & Montironi, R. (2016). Metabolic phenotype of bladder cancer. Cancer Treatment Reviews, 45, 46-57. https://doi.org/10.1016/j.ctrv.2016.03.005