ArticleThe Journal of biological chemistry2014
Intracellular carbonic anhydrase activity sensitizes cancer cell pH signaling to dynamic changes in CO2 partial pressure.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 44 citations in OpenAlex.
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- How protons pave the way to aggressive cancers.Nature reviews. Cancer · 2023Review
- The carbonic anhydrase inhibitor acetazolamide inhibits urinary bladder cancers via suppression of β-catenin signaling.Cancer science · 2022Article
- What do cellular responses to acidity tell us about cancer?Cancer metastasis reviews · 2021Review
- Carbonic Anhydrases II and IX in Non-ampullary Duodenal Adenomas and Adenocarcinoma.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2021Article
- Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases.International journal of molecular sciences · 2021Review
- Tumour acidosis evaluated in vivo by MRI-CEST pH imaging reveals breast cancer metastatic potential.British journal of cancer · 2021Article
- Targeting of Evolutionarily Acquired Cancer Cell Phenotype by Exploiting pHi-Metabolic Vulnerabilities.Cancers · 2020Article
- Interplay between Carbonic Anhydrases and Metallothioneins: Structural Control of Metalation.International journal of molecular sciences · 2020Review
- Dietary cadmium chloride impairs shell biomineralization by disrupting the metabolism of the eggshell gland in laying hens.Journal of animal science · 2020Article
- Hypothesis: Potentially Systemic Impacts of Elevated COFrontiers in public health · 2020Article
- Using bidirectional chemical exchange for improved hyperpolarized [Magnetic resonance in medicine · 2019Article
- Spatiotemporal pH Heterogeneity as a Promoter of Cancer Progression and Therapeutic Resistance.Cancers · 2019Review
- Multiomic Profiling of Tyrosine Kinase Inhibitor-Resistant K562 Cells Suggests Metabolic Reprogramming To Promote Cell Survival.Journal of proteome research · 2019Article
- Dichloroacetate and Salinomycin Exert a Synergistic Cytotoxic Effect in Colorectal Cancer Cell Lines.Scientific reports · 2018Article
- Carbonic anhydrases II, IX, and XII in Barrett's esophagus and adenocarcinoma.Virchows Archiv : an international journal of pathology · 2018Article
- Gas Partial Pressure in Cultured Cells: Patho-Physiological Importance and Methodological Approaches.Frontiers in physiology · 2018Review
- Tumour acidosis: from the passenger to the driver's seat.Nature reviews. Cancer · 2017Review
- Connexin-43 channels are a pathway for discharging lactate from glycolytic pancreatic ductal adenocarcinoma cells.Oncogene · 2017Article
- Carbonic anhydrase 2 is a novel invasion-associated factor in urinary bladder cancers.Cancer science · 2017Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Carbonic anhydrase (CA) enzymes catalyze the chemical equilibration among CO2, HCO3(-) and H(+). Intracellular CA (CAi) isoforms are present in certain types of cancer, and growing evidence suggests that low levels correlate with disease severity. However, their physiological role remains unclear. Cancer cell CAi activity, measured as cytoplasmic CO2 hydration rate (kf), ranged from high in colorectal HCT116 (∼2 s(-1)), bladder RT112 and colorectal HT29, moderate in fibrosarcoma HT1080 to negligible (i.e. spontaneous kf = 0.18 s(-1)) in cervical HeLa and breast MDA-MB-468 cells. CAi activity in cells correlated with CAII immunoreactivity and enzymatic activity in membrane-free lysates, suggesting that soluble CAII is an important intracellular isoform. CAi catalysis was not obligatory for supporting acid extrusion by H(+) efflux or HCO3(-) influx, nor for maintaining intracellular pH (pHi) uniformity. However, in the absence of CAi activity, acid loading from a highly alkaline pHi was rate-limited by HCO3(-) supply from spontaneous CO2 hydration. In solid tumors, time-dependence of blood flow can result in fluctuations of CO2 partial pressure (pCO2) that disturb cytoplasmic CO2-HCO3(-)-H(+) equilibrium. In cancer cells with high CAi activity, extracellular pCO2 fluctuations evoked faster and larger pHi oscillations. Functionally, these resulted in larger pH-dependent intracellular [Ca(2+)] oscillations and stronger inhibition of the mTORC1 pathway reported by S6 kinase phosphorylation. In contrast, the pHi of cells with low CAi activity was less responsive to pCO2 fluctuations. Such low pass filtering would "buffer" cancer cell pHi from non-steady-state extracellular pCO2. Thus, CAi activity determines the coupling between pCO2 (a function of tumor perfusion) and pHi (a potent modulator of cancer cell physiology).
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