Stable Isotope Tracing Uncovers Reduced γ/β-ATP Turnover and Metabolic Flux Through Mitochondrial-Linked Phosphotransfer Circuits in Aggressive Breast Cancer Cells

Aleksandr Klepinin, Sten Miller, Indrek Reile, Marju Puurand, Egle Rebane-Klemm, Ljudmila Klepinina, Heiki Vija, Song Zhang, Andre Terzic, Petras P Dzeja, Tuuli Kaambre

Research output: Contribution to journalArticlepeer-review

Abstract

Changes in dynamics of ATP γ- and β-phosphoryl turnover and metabolic flux through phosphotransfer pathways in cancer cells are still unknown. Using 18O phosphometabolite tagging technology, we have discovered phosphotransfer dynamics in three breast cancer cell lines: MCF7 (non-aggressive), MDA-MB-231 (aggressive), and MCF10A (control). Contrary to high intracellular ATP levels, the 18O labeling method revealed a decreased γ- and β-ATP turnover in both breast cancer cells, compared to control. Lower β-ATP[18O] turnover indicates decreased adenylate kinase (AK) flux. Aggressive cancer cells had also reduced fluxes through hexokinase (HK) G-6-P[18O], creatine kinase (CK) [CrP[18O], and mitochondrial G-3-P[18O] substrate shuttle. Decreased CK metabolic flux was linked to the downregulation of mitochondrial MTCK1A in breast cancer cells. Despite the decreased overall phosphoryl flux, overexpression of HK2, AK2, and AK6 isoforms within cell compartments could promote aggressive breast cancer growth.

Original languageEnglish (US)
Article number892195
JournalFrontiers in Oncology
Volume12
DOIs
StatePublished - May 31 2022

Keywords

  • 18 O stable isotope labeling technology
  • adenylate kinase
  • creatine kinase
  • glycolysis
  • oxidative phosphorylation
  • phosphotransfer network
  • triple-negative breast cancer
  • γ-and β-ATP phosphoryl turnover

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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