title: Metabolic phenotype of bladder cancer.
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.
authors.affiliation: Division of Oncology, S.Orsola-Malpighi Hospital, Bologna, Italy. Electronic address: fmassari79@gmail.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Massari
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ciccarese
authors.affiliation: Medical Oncology, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Santoni
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Iacovelli
authors.affiliation: Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, AOU Ospedali Riuniti, Ancona, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mazzucchelli
authors.affiliation: Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Piva
authors.affiliation: Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, AOU Ospedali Riuniti, Ancona, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Scarpelli
authors.affiliation: Medical Oncology, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Berardi
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.affiliation: Pathology Service, Champalimaud Clinical Center, Lisbon, Portugal.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopez-Beltran
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, AOU Ospedali Riuniti, Ancona, Italy. Electronic address: r.montironi@univpm.it.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Montironi
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015533:Transcriptional Activation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495677:SLC2A1 protein, human; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Bladder cancer; Metabolic pathway; Metabolism; Novel target