The glucose and lipid metabolism reprogramming is gradedependent in clear cell renal cell carcinoma primary cultures and is targetable to modulate cell viability and proliferation

Cristina Bianchi, Chiara Meregalli, Silvia Bombelli, Vitalba Di Stefano, Francesco Salerno, Barbara Torsello, Sofia De Marco, Giorgio Bovo, Ingrid Cifola, Eleonora Mangano, Cristina Battaglia, Guido Strada, Giuseppe Lucarelli, Robert H Weiss, Roberto A. Perego

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Clear cell renal cell carcinoma (ccRCC) has a poor prognosis despite novel biological targeted therapies. Tumor aggressiveness and poor survival may correlate with tumor grade at diagnosis and with complex metabolic alterations, also involving glucose and lipid metabolism. However, currently no grade-specific metabolic therapy addresses these alterations. Here we used primary cell cultures from ccRCC of low- and high-grade to investigate the effect on energy state and reduced pyridine nucleotide level, and on viability and proliferation, of specific inhibition of glycolysis with 2-deoxy-D-glucose (2DG), or fatty acid oxidation with Etomoxir. Our primary cultures retained the tissue grade-dependent modulation of lipid and glycogen storage and aerobic glycolysis (Warburg effect). 2DG affected lactate production, energy state and reduced pyridine nucleotide level in high-grade ccRCC cultures, but the energy state only in low-grade. Rather, Etomoxir affected energy state in high-grade and reduced pyridine nucleotide level in low-grade cultures. Energy state and reduced pyridine nucleotide level were evaluated by ATP and reduced 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) dye quantification, respectively. 2DG treatment impaired cell proliferation and viability of low-grade ccRCC and normal cortex cultures, whereas Etomoxir showed a cytostatic and cytotoxic effect only in high-grade ccRCC cultures. Our data indicate that in ccRCC the Warburg effect is a grade-dependent feature, and fatty acid oxidation can be activated for different grade-dependent metabolic needs. A possible grade-dependent metabolic therapeutic approach in ccRCC is also highlighted.

Original languageEnglish (US)
Pages (from-to)113502-113515
Number of pages14
JournalOncotarget
Volume8
Issue number69
DOIs
StatePublished - Jan 1 2017

Keywords

  • Fuhrman grade
  • Glucose and lipid metabolism reprogramming
  • Primary cell cultures
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Oncology

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    Bianchi, C., Meregalli, C., Bombelli, S., Di Stefano, V., Salerno, F., Torsello, B., De Marco, S., Bovo, G., Cifola, I., Mangano, E., Battaglia, C., Strada, G., Lucarelli, G., Weiss, R. H., & Perego, R. A. (2017). The glucose and lipid metabolism reprogramming is gradedependent in clear cell renal cell carcinoma primary cultures and is targetable to modulate cell viability and proliferation. Oncotarget, 8(69), 113502-113515. https://doi.org/10.18632/oncotarget.23056