Hypoxia inducible factor-1 alpha as a therapeutic target in multiple myeloma

Enrica Borsi, Giulia Perrone, Carolina Terragna, Marina Martello, Angela F. Dico, Giancarlo Solaini, Alessandra Baracca, Gianluca Sgarbi, Gianandrea Pasquinelli, Sabrina Valente, Elena Zamagni, Paola Tacchetti, Giovanni Martinelli, Michele Cavo

Research output: Contribution to journalArticlepeer-review

Abstract

The increasing importance of hypoxia-inducible factor-1a (HIF-1a) in tumorigenesis raises the possibility that agents which specifically inhibit this transcription factor, would provide significant therapeutic benefit. The constitutive expression of HIF-1a in about 35% of Multiple Myeloma (MM) patients suggests HIF- 1a suppression might be part of a therapeutic strategy. Accordingly, we explored the effect of EZN-2968, a small 3rd generation antisense oligonucleotide against HIF-1a, in a panel of MM cell lines and primary patients samples. Here, we demonstrated that EZN-2968 is highly specific for HIF-1a mRNA and that exposure of MM cells to EZN-2968 resulted in an efficient and homogeneous loading of the cells showing a long lasting low HIF-1a protein level. In MM cells, HIF-1a suppression induced a permanent cell cycle arrest by prolonging S-phase through cyclin A modulation and in addition it induced a mild apoptotic cell death. Moreover, HIF-1a suppression caused a metabolic shift that leaded to increased production of ATP by oxidative phosphorylation (i.e. Warburg effect reversion), that was confirmed by the observed mitochondrial membrane potential decrease. These results show that HIF-1a is an important player in MM homeostasis and that its inhibition by small antisense oligonucleotides provides a rationale for novel therapeutic strategy to improving MM treatment.

Original languageEnglish
Pages (from-to)1779-1792
Number of pages14
JournalOncotarget
Volume5
Issue number7
Publication statusPublished - 2014

Keywords

  • Cell cycle
  • HIF-1a
  • Mitochondria
  • Multiple myeloma
  • Warburg effect

ASJC Scopus subject areas

  • Oncology

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