TY - JOUR
T1 - Stable Isotope Tracing Uncovers Reduced γ/β-ATP Turnover and Metabolic Flux Through Mitochondrial-Linked Phosphotransfer Circuits in Aggressive Breast Cancer Cells
AU - Klepinin, Aleksandr
AU - Miller, Sten
AU - Reile, Indrek
AU - Puurand, Marju
AU - Rebane-Klemm, Egle
AU - Klepinina, Ljudmila
AU - Vija, Heiki
AU - Zhang, Song
AU - Terzic, Andre
AU - Dzeja, Petras
AU - Kaambre, Tuuli
N1 - Funding Information:
This work was supported by the Estonian Research Council grants PRG1035, PSG11, PUTJD963 and the mobility grant MOBTP51; the National Institutes of Health (R01 HL134664 and R01 HL85744) and Marriott Family Foundation; as well as Estonia national scholarship program Kristjan Jaak, which is funded and managed by Archimedes Foundation in collaboration with the Estonian Ministry of Education and Research.
Publisher Copyright:
Copyright © 2022 Klepinin, Miller, Reile, Puurand, Rebane-Klemm, Klepinina, Vija, Zhang, Terzic, Dzeja and Kaambre.
PY - 2022/5/31
Y1 - 2022/5/31
N2 - 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.
AB - 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.
KW - 18 O stable isotope labeling technology
KW - adenylate kinase
KW - creatine kinase
KW - glycolysis
KW - oxidative phosphorylation
KW - phosphotransfer network
KW - triple-negative breast cancer
KW - γ-and β-ATP phosphoryl turnover
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U2 - 10.3389/fonc.2022.892195
DO - 10.3389/fonc.2022.892195
M3 - Article
AN - SCOPUS:85132436614
SN - 2234-943X
VL - 12
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 892195
ER -