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Intracellular NAD(+) depletion induces autophagic death in multiple myeloma cells

Michele Cea1, Antonia Cagnetta, Franco Patrone

  • 1LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. michele_cea@dfci.harvard.edu

Autophagy
|December 11, 2012
PubMed

Insights

This study reveals that targeting nicotinamide adenine dinucleotide (NAD+) levels in multiple myeloma (MM) cells triggers cell death. This discovery offers a new therapeutic strategy for treating this incurable B-cell malignancy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Multiple myeloma (MM) is a fatal B-cell malignancy with limited treatment options.
  • Cancer cells, including MM, exhibit elevated nicotinamide adenine dinucleotide (NAD+) metabolism.
  • Targeting NAD+ biosynthesis presents a potential therapeutic strategy for MM.

Purpose of the Study:

  • To investigate the role of intracellular NAD+ levels in MM cell survival.
  • To explore the anti-MM effects of the NAD+-depleting agent FK866.
  • To elucidate the mechanisms by which FK866 induces cell death in MM.

Main Methods:

  • Utilized FK866, an inhibitor of NAD+ biosynthesis.
  • Investigated autophagic cell death pathways, including transcription factor EB (TFEB) and PI3K-MTORC1 signaling.
  • Assessed the impact of FK866 on intracellular NAD+ levels and MM cell viability.

Main Results:

  • FK866 significantly reduced intracellular NAD+ levels in MM cells.
  • FK866 treatment induced autophagic cell death through both TFEB-dependent and -independent pathways.
  • A direct link between NAD+ depletion and autophagy was established in MM.

Conclusions:

  • Intracellular NAD+ depletion is a viable strategy for inducing cell death in multiple myeloma.
  • FK866 triggers autophagic cell death in MM via distinct molecular mechanisms.
  • Targeting NAD+ metabolism offers a novel therapeutic avenue for managing multiple myeloma.

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