Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases

Becker, Holger M.; Deitmer, Joachim W.

doi:10.3390/ijms22063171

Cited by 28 publications

(18 citation statements)

References 158 publications

(126 reference statements)

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“…The increase in intracellular pH and decreased in extracellular pH found in IVF-generated embryos is particularly important, because it confirms the profound alteration in embryo metabolism. In fact, cancer cells are known to have higher intracellular pH and lower extracellular pH ( Webb et al, 2011 ) and regulation of intra- and extracellular pH is considered essential for cellular physiological and metabolic function ( Becker and Deitmer, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production

Lee

Liu

Jimenez-Morales

et al. 2022

eLife

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In vitro fertilization (IVF) has resulted in the birth of over 8 million children. Although most of IVF-conceived children are healthy, several studies suggest an increased risk of altered growth rate, cardiovascular dysfunction, and glucose intolerance in this population compared to naturally conceived children. However, a clear understanding of how embryonic metabolism is affected by culture condition and how embryos reprogram their metabolism is unknown. Here, we studied oxidative stress and metabolic alteration in blastocysts conceived by natural mating or by IVF and culture in physiologic (5%) or atmospheric (20%) oxygen. We found that IVF-generated blastocyst manifest increased reactive oxygen species, oxidative damage to DNA/lipid/proteins, and reduction in glutathione. Metabolic analysis revealed IVF-generated blastocysts display decreased mitochondria respiration and increased glycolytic activity suggestive of enhanced Warburg metabolism. These findings were corroborated by altered intracellular and extracellular pH and increased intracellular lactate levels in IVF-generated embryos. Comprehensive proteomic analysis and targeted immunofluorescence showed reduction of LDH-B and MCT1, enzymes involved in lactate metabolism. Importantly, these enzymes remained downregulated in tissues of adult IVF-conceived mice, suggesting that metabolic alterations in IVF-generated embryos may result in alteration in lactate metabolism. These findings suggest that alterations in lactate metabolism is a likely mechanism involved in genomic reprogramming and could be involved in the developmental origin of health and disease.

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Section: Discussionmentioning

confidence: 99%

Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production

Lee

Liu

Jimenez-Morales

et al. 2022

eLife

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“…Tumor hypoxia causes the metabolic shift towards acidity where proton (H + ) accumulation is proportional to O 2 levels [ 454 ]. Excess intracellular protons are often extruded into extracellular space via different mechanisms [ 455 ] including membrane transporters [ 456 ], carbonic anhydrase enzymes [ 457 ], and lysosomes [ 458 ], or sequestered in proton sinks [ 459 ]. The ensuing acidic pH e may directly interfere with the efficacy of weakly basic chemotherapeutic drugs by impeding their intracellular distribution through “ion trapping” [ 460 ].…”

Section: Melatonin May Promote Prp Physiological Functions and Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

Loh¹,

Reíter

2022

Molecules

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The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.

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“… 1 , 2 In humans, there are 15 distinct CA isoforms, each with its own molecular features, subcellular localisation, and tissue distribution. 3 , 4 These enzymes are required for a variety of physiological and cellular activities, including electrolyte secretion, acid–base balance, carbon dioxide transport, and biosynthetic pathways. 5 , 6 Compared to normal tissues, where CA IX expression is modest, the variety of solid tumours have some of the most overexpressed transmembrane proteins.…”

Section: Introductionmentioning

confidence: 99%

Dependence on linkers’ flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents

Tawfik

Belal

Abourehab

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Herein we reported the design and synthesis of two series comprising twenty-two benzenesulfonamides that integrate the s -triazine moiety. Target compounds successfully suppressed the hCA IX, with IC 50 ranging from 28.6 to 871 nM. Compounds 5d , 11b , 5b , and 7b were the most active analogues, which inhibited hCA IX isoform in the low nanomolar range ( K I = 28.6, 31.9, 33.4, and 36.6 nM, respectively). Furthermore, they were assessed for their cytotoxic activity against a panel of 60 cancer cell lines following US-NCI protocol. According to five-dose assay, 13c showed significant anticancer activity than 5c with GI 50 -MID values of 25.08 and 189.01 µM, respectively. Additionally, 13c ’s effects on wound healing, cell cycle disruption, and apoptosis induction in NCI-H460 cancer cells were examined. Further, docking studies combined with molecular dynamic simulation showed a stable complex with high binding affinity of 5d to hCA IX, exploiting a favourable H-bond and lipophilic interactions. HIGHLIGHTS Carbonic anhydrase (CA) inhibitors comprising rigid and flexible linkers were developed. Compound 5d is the most potent CA IX inhibitor in the study (IC50: 28.6 nM). Compounds 5c and 13c displayed the greatest antiproliferative activity towards 60 cell lines. Compound 13c exposed constructive outcomes on normal cell lines, metastasis, and wound healing. Molecular docking and molecular dynamics (MDs) simulation was utilised to study binding mode.

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Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases

Cited by 28 publications

References 158 publications

Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production

Murine blastocysts generated by in vitro fertilization show increased Warburg metabolism and altered lactate production

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

Dependence on linkers’ flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents

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