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

40 Citations (Scopus)

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

Fingerprint

Urinary Bladder Neoplasms
Glycolysis
Phenotype
Glycogen
Neoplasms
amylo-1,6-glucosidase
Glycine
Glycogen Debranching Enzyme System
Lactic Acid
Fatty Acids
Glucose Transporter Type 1
Glycine Hydroxymethyltransferase
Cell Proliferation
Glucosidases
Purine Nucleotides
Pentoses
Glycogen Phosphorylase
Glucose
Hypoxia-Inducible Factor 1
Pentose Phosphate Pathway

Keywords

  • Bladder cancer
  • Metabolic pathway
  • Metabolism
  • Novel target

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

Cite this

Massari, F., Ciccarese, C., Santoni, M., Iacovelli, R., Mazzucchelli, R., Piva, F., ... Montironi, R. (2016). Metabolic phenotype of bladder cancer. Cancer Treatment Reviews, 45, 46-57. https://doi.org/10.1016/j.ctrv.2016.03.005

Metabolic phenotype of bladder cancer. / Massari, Francesco; Ciccarese, Chiara; Santoni, Matteo; Iacovelli, Roberto; Mazzucchelli, Roberta; Piva, Francesco; Scarpelli, Marina; Berardi, Rossana; Tortora, Giampaolo; Lopez-Beltran, Antonio; Cheng, Liang; Montironi, Rodolfo.

In: Cancer Treatment Reviews, Vol. 45, 01.04.2016, p. 46-57.

Research output: Contribution to journalArticle

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, vol. 45, pp. 46-57. https://doi.org/10.1016/j.ctrv.2016.03.005
Massari F, Ciccarese C, Santoni M, Iacovelli R, Mazzucchelli R, Piva F et al. Metabolic phenotype of bladder cancer. Cancer Treatment Reviews. 2016 Apr 1;45:46-57. https://doi.org/10.1016/j.ctrv.2016.03.005
Massari, Francesco ; Ciccarese, Chiara ; Santoni, Matteo ; Iacovelli, Roberto ; Mazzucchelli, Roberta ; Piva, Francesco ; Scarpelli, Marina ; Berardi, Rossana ; Tortora, Giampaolo ; Lopez-Beltran, Antonio ; Cheng, Liang ; Montironi, Rodolfo. / Metabolic phenotype of bladder cancer. In: Cancer Treatment Reviews. 2016 ; Vol. 45. pp. 46-57.
@article{b4fbdcba5cb64cbc93bc57ab3c018cac,
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.",
keywords = "Bladder cancer, Metabolic pathway, Metabolism, Novel target",
author = "Francesco Massari and Chiara Ciccarese and Matteo Santoni and Roberto Iacovelli and Roberta Mazzucchelli and Francesco Piva and Marina Scarpelli and Rossana Berardi and Giampaolo Tortora and Antonio Lopez-Beltran and Liang Cheng and Rodolfo Montironi",
year = "2016",
month = "4",
day = "1",
doi = "10.1016/j.ctrv.2016.03.005",
language = "English (US)",
volume = "45",
pages = "46--57",
journal = "Cancer Treatment Reviews",
issn = "0305-7372",
publisher = "W.B. Saunders Ltd",

}

TY - JOUR

T1 - Metabolic phenotype of bladder cancer

AU - Massari, Francesco

AU - Ciccarese, Chiara

AU - Santoni, Matteo

AU - Iacovelli, Roberto

AU - Mazzucchelli, Roberta

AU - Piva, Francesco

AU - Scarpelli, Marina

AU - Berardi, Rossana

AU - Tortora, Giampaolo

AU - Lopez-Beltran, Antonio

AU - Cheng, Liang

AU - Montironi, Rodolfo

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

KW - Bladder cancer

KW - Metabolic pathway

KW - Metabolism

KW - Novel target

UR - http://www.scopus.com/inward/record.url?scp=84960368792&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960368792&partnerID=8YFLogxK

U2 - 10.1016/j.ctrv.2016.03.005

DO - 10.1016/j.ctrv.2016.03.005

M3 - Article

C2 - 26975021

AN - SCOPUS:84960368792

VL - 45

SP - 46

EP - 57

JO - Cancer Treatment Reviews

JF - Cancer Treatment Reviews

SN - 0305-7372

ER -