Reversal of the glycolytic phenotype of primary effusion lymphoma cells by combined targeting of cellular metabolism and PI3K/Akt/mTOR signaling

Laura Mediani, Federica Gibellini, Jessika Bertacchini, Chiara Frasson, Raffaella Bosco, Benedetta Accordi, Giuseppe Basso, Massimo Bonora, Maria Luisa Calabrò, Adriana Mattiolo, Gianluca Sgarbi, Alessandra Baracca, Paolo Pinton, Giovanni Riva, Enrico Rampazzo, Luca Petrizza, Luca Prodi, Daniela Milani, Mario Luppi, Leonardo PotenzaAnto De Pol, Lucio Cocco, Silvano Capitani, Sandra Marmiroli

Research output: Contribution to journalArticlepeer-review

Abstract

PEL is a B-cell non-Hodgkin lymphoma, occurring predominantly as a lymphomatous effusion in body cavities, characterized by aggressive clinical course, with no standard therapy. Based on previous reports that PEL cells display a Warburg phenotype, we hypothesized that the highly hypoxic environment in which they grow in vivo makes them more reliant on glycolysis, and more vulnerable to drugs targeting this pathway. We established here that indeed PEL cells in hypoxia are more sensitive to glycolysis inhibition. Furthermore, since PI3K/Akt/mTOR has been proposed as a drug target in PEL, we ascertained that pathway-specific inhibitors, namely the dual PI3K and mTOR inhibitor, PF-04691502, and the Akt inhibitor, Akti 1/2, display improved cytotoxicity to PEL cells in hypoxic conditions. Unexpectedly, we found that these drugs reduce lactate production/extracellular acidification rate, and, in combination with the glycolysis inhibitor 2-deoxyglucose (2-DG), they shift PEL cells metabolism from aerobic glycolysis towards oxidative respiration. Moreover, the associations possess strong synergistic cytotoxicity towards PEL cells, and thus may reduce adverse reaction in vivo, while displaying very low toxicity to normal lymphocytes. Finally, we showed that the association of 2-DG and PF-04691502 maintains its cytotoxic and proapoptotic effect also in PEL cells co-cultured with human primary mesothelial cells, a condition known to mimic the in vivo environment and to exert a protective and pro-survival action. All together, these results provide a compelling rationale for the clinical development of new therapies for the treatment of PEL, based on combined targeting of glycolytic metabolism and constitutively activated signaling pathways.

Original languageEnglish
Pages (from-to)5521-5537
Number of pages17
JournalOncotarget
Volume7
Issue number5
DOIs
Publication statusPublished - 2016

Keywords

  • Glycolyis inhibitors
  • Hypoxia
  • PEL/non-Hodgkin lymphoma
  • PI3K/Akt/mTOR inhibitors
  • Warburg phenotype

ASJC Scopus subject areas

  • Oncology

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