1. Academic Validation
  2. Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition

Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition

  • Blood. 2012 Oct 25;120(17):3519-29. doi: 10.1182/blood-2012-03-416776.
Michele Cea 1 Antonia Cagnetta Mariateresa Fulciniti Yu-Tzu Tai Teru Hideshima Dharminder Chauhan Aldo Roccaro Antonio Sacco Teresa Calimeri Francesca Cottini Jana Jakubikova Sun-Young Kong Franco Patrone Alessio Nencioni Marco Gobbi Paul Richardson Nikhil Munshi Kenneth C Anderson
Affiliations

Affiliation

  • 1 LeBow Institute for Myeloma Therapeutics, Harvard Medical School, Boston, MA, USA.
Abstract

Malignant cells have a higher nicotinamide adenine dinucleotide (NAD(+)) turnover rate than normal cells, making this biosynthetic pathway an attractive target for Cancer treatment. Here we investigated the biologic role of a rate-limiting Enzyme involved in NAD(+) synthesis, NAMPT, in multiple myeloma (MM). Nampt-specific chemical inhibitor FK866 triggered cytotoxicity in MM cell lines and patient MM cells, but not normal donor as well as MM patients PBMCs. Importantly, FK866 in a dose-dependent fashion triggered cytotoxicity in MM cells resistant to conventional and novel anti-MM therapies and overcomes the protective effects of cytokines (IL-6, IGF-1) and bone marrow stromal cells. NAMPT knockdown by RNAi confirmed its pivotal role in maintenance of both MM cell viability and intracellular NAD(+) stores. Interestingly, cytotoxicity of FK866 triggered Autophagy, but not Apoptosis. A transcriptional-dependent (TFEB) and independent (PI3K/mTORC1) activation of Autophagy mediated FK866 MM cytotoxicity. Finally, FK866 demonstrated significant anti-MM activity in a xenograft-murine MM model, associated with down-regulation of ERK1/2 phosphorylation and proteolytic cleavage of LC3 in tumor cells. Our data therefore define a key role of NAMPT in MM biology, providing the basis for a novel targeted therapeutic approach.

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