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

Michele Cea, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3519-3529
Number of pages11
JournalBlood
Volume120
Issue number17
DOIs
Publication statusPublished - Oct 25 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Cea, M., Cagnetta, A., Fulciniti, M., Tai, Y. T., Hideshima, T., Chauhan, D., Roccaro, A., Sacco, A., Calimeri, T., Cottini, F., Jakubikova, J., Kong, S. Y., Patrone, F., Nencioni, A., Gobbi, M., Richardson, P., Munshi, N., & Anderson, K. C. (2012). Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition. Blood, 120(17), 3519-3529. https://doi.org/10.1182/blood-2012-03-416776