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Oligomycin-induced Bioenergetic Adaptation in Cancer Cells with Heterogeneous Bioenergetic Organization
Open accessAbstract
Cancer cells constantly adapt to oxidative phosphorylation (OXPHOS) suppression resulting from hypoxia or mitochondria defects. Under the OXPHOS suppression, AMP-activated protein kinase (AMPK) regulates global metabolism adjustments, but its activation has been found to be transient. Whether cells can maintain cellular ATP homeostasis and survive beyond the transient AMPK activation is not known. Here, we study the bioenergetic adaptation to the OXPHOS inhibitor oligomycin in a group of cancer cells. We found that oligomycin at 100 ng/ml completely inhibits OXPHOS activity in 1 h and induces various levels of glycolysis gains by 6 h, from which we calculate the bioenergetic organizations of cancer cells. In glycolysis-dominant cells, oligomycin does not induce much energy stress as measured by glycolysis acceleration, ATP imbalance, AMPK activation, AMPK substrate acetyl-CoA carboxylase phosphorylation at Ser(79), and cell growth inhibition. In OXPHOS-dependent LKB1 wild type cells, oligomycin induces 5-8% ATP drops and transient AMPK activation during the initial 1-2 h. After AMPK activation is completed, oligomycin-induced increase of acetyl-CoA carboxylase phosphorylation at Ser(79) is still detected, and cellular ATP is back at preoligomycin treatment levels by sustained elevation of glycolysis. Cell growth, however, is inhibited without an increase in cell death and alteration in cell cycle distribution. In OXPHOS-dependent LKB1-null cells, no AMPK activation by oligomycin is detected, yet cells still show a similar adaptation. We also demonstrate that the adaptation to oligomycin does not invoke activation of hypoxia-induced factor. Our data suggest that cancer cells may grow and survive persistent OXPHOS suppression through an as yet unidentified regulatory mechanism.
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In the citing paper
“the use of this oligomycin concentration is common in the literature and causes a minor nonspecific effect on mitochondrial and cellular function [15,25,26,27].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [15]
In the citing paper
“Notably, cultured cancer cells were able to grow and survive even under the inhibition of oxidative phosphorylation by oligomycin [15].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [15]
In the citing paper
“However, we used 10 times more oligomycin in our experiments since this oligomycin concentration elicits minor nonspecific effects and it is common in the literature [15,25,26,27].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [15]
In the citing paper
“These findings confirm previous studies that analyzed inhibition of either glycolysis or OXPHOS, and observed an increase in the activity of the other pathway (Hao et al., 2010; Jose et al., 2011; Birsoy et al., 2014; Dykens et al., 2008).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Hao et al., 2010
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Metadata
- Authors
- Hao, W., Chang, C.-P. B., Tsao, C.-C., & Xu, J.
- Affiliations
- Wyeth (US)
- Corresponding author
- Hao, Wenshan
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 285
- Issue
- 17
- Pages
- 12647-12654
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2857128
- OpenAlex
- W2009114717
- Cited by
- 138
- References
- 24
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 12 · 2023: 7 · 2022: 8 · 2021: 11 · 2020: 10 · 2019: 13 · 2018: 8 · 2017: 8 · 2016: 6 · 2015: 3 · 2014: 12 · 2013: 10 · 2012: 8
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- oligomycin, cancer cells, oxidative phosphorylation inhibition, AMPK, acetyl-CoA carboxylase, glycolysis, ATP homeostasis, LKB1, hypoxia, energy stress, cell growth inhibition
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Acetyl-CoA Carboxylase, Adenosine Triphosphate, Dose-Response Relationship, Drug, Enzyme Activation, Glycolysis, Humans, Mitochondria, Neoplasm Proteins, Neoplasms, Oligomycins, Oxidative Phosphorylation, Phosphorylation, Stress, Physiological, Time Factors, Uncoupling Agents, Cell Hypoxia, Protein Serine-Threonine Kinases, Cell Line, Tumor, AMP-Activated Protein Kinases
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