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Updated: Jun 15, 2025

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Transcriptional Isoforms of NAD+ kinase regulate oxidative stress resistance and melanoma metastasis

Graciela Cascio1, Kelsey N Aguirre1, Kellsey P Church1

  • 1Sandra and Edward Meyer Cancer Center, 413 East 69th Street, Belfer Research Building, Weill Cornell Medicine, 10021, New York, NY, USA.

Redox Biology
|August 21, 2024
PubMed

Insights

Metastatic melanoma cells increase antioxidant capacity via NAD+ kinase (NADK) Isoform 3. This isoform enhances oxidative stress resistance and promotes cancer metastasis, offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Metastasizing cancer cells face oxidative stress, necessitating metabolic adaptations for survival.
  • Nicotinamide adenine dinucleotide phosphate (NADPH) is crucial for antioxidant regeneration and plays a role in metastasis.
  • Metastatic melanoma cells exhibit elevated NADPH and NADP+ levels, indicating increased de novo NADP+ biosynthesis.

Purpose of the Study:

  • To investigate the role of NAD+ kinase (NADK) isoforms in metastatic melanoma.
  • To determine the specific NADK isoform responsible for increased NADP+ biosynthesis and its impact on metastasis.

Main Methods:

  • Differential expression analysis of NADK isoforms in metastatic melanoma cells.
  • Functional assays to assess the impact of NADK isoforms on NADP(H) pools, oxidative stress resistance, and metastatic colonization.
  • Investigating the transcriptional regulation of NADK Isoform 3 by oxidative stress and NRF2.

Main Results:

  • NAD+ kinase (NADK) Isoform 3 is specifically upregulated in metastatic melanoma cells.
  • NADK Isoform 3 is more effective than Isoform 1 in expanding NADP(H) pools and enhancing oxidative stress resistance.
  • Oxidative stress upregulates NADK Isoform 3 transcriptionally via NRF2, promoting metastatic colonization.

Conclusions:

  • NADK isoforms play a previously unrecognized role in oxidative stress resistance and cancer metastasis.
  • NADK Isoform 3 is a key mediator of metastatic melanoma cell adaptation and progression.
  • NADK Isoform 3 represents a promising therapeutic target for metastatic melanoma.
Keywords:
AntioxidantsMetastasisNADKNADP(+)Oxidative stress

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