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Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
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NNMT-DNMT1 Axis is Essential for Maintaining Cancer Cell Sensitivity to Oxidative Phosphorylation Inhibition

Changqing Wu1, Yu'e Liu1, Wenju Liu2

  • 1Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, 200092, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|November 16, 2022
PubMed

Insights

Cancer cells

Area of Science:

  • Cancer Biology
  • Metabolic Pathways
  • Molecular Mechanisms

Background:

  • Understanding cancer cell sensitivity to oxidative phosphorylation (OXPHOS) inhibition is crucial for developing targeted therapies.
  • The molecular mechanisms governing this sensitivity are not fully understood.
  • Identifying biomarkers for OXPHOS-targeting treatments is a key challenge.

Purpose of the Study:

  • To identify molecular mechanisms determining cancer cell sensitivity to OXPHOS inhibition.
  • To screen for cancer cell lines with varying sensitivity to OXPHOS inhibitors.
  • To evaluate the NNMT-DNMT1 axis as a predictor for OXPHOS inhibitor efficacy.

Main Methods:

  • Screening of cancer cell lines for sensitivity to OXPHOS inhibition.
  • Analysis of nicotinamide N-methyltransferase (NNMT) and DNA methyltransferase 1 (DNMT1) expression.
  • In vitro experiments involving NNMT overexpression and DNMT1 inhibition.
  • In vivo studies using mouse tumor xenografts with OXPHOS inhibitors (Gboxin, Berberine).
  • Retrospective analysis of clinical trial data from colorectal adenoma patients.

Main Results:

  • OXPHOS inhibition-sensitive cells exhibit higher OXPHOS activity and lower NNMT expression.
  • NNMT expression inversely correlates with OXPHOS inhibition sensitivity by regulating S-adenosyl methionine (SAM) levels.
  • DNMT1 expression positively correlates with OXPHOS inhibition sensitivity.
  • NNMT overexpression or DNMT1 inhibition confers resistance to OXPHOS inhibitors.
  • OXPHOS inhibitors effectively reduced tumor growth in sensitive xenografts.
  • Berberine treatment decreased recurrence in patients with NNMTlow/DNMT1high colorectal adenomas.

Conclusions:

  • The NNMT-DNMT1 axis is a critical determinant of cancer cell reliance on mitochondrial OXPHOS.
  • NNMT and DNMT1 serve as reliable biomarkers for predicting response to OXPHOS-targeting cancer therapies.
  • Targeting OXPHOS presents a promising therapeutic strategy for specific cancer subtypes.
Keywords:
DNA methylationN-methyltransferase (NNMT)S-adenosyl methionine (SAM)biomarkercanceroxidative phosphorylation (OXPHOS)

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