What is it about?
In previous work we have shown that Increased intracellular chloride (through CFTR or other chloride channels) induce a proinflammatory state that leads to an autocrine IL-1b loop that induce a mitochondrial failure. Here we show that cells with impaired CFTR chloride channel activity, produce Warburg-like effect that promotes an increased LDH expression and activity, with lactate hypersecretion. The lactate hypersecretion might lead to a reduce extracellular pH when the buffer capacity of the extracellular environment is exceeded.
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Why is it important?
As it was previously shown, this chronic proinflammatory state and the mitochondrial failure induced by the CFTR failure is due to the increased Cl- accumulation, although the specific mechanism for the increased LDH activity is yet unknown. It is accompanied by a proinflammatory state with increased lactic acid secretion and extracellular pH reduction, which might explain the increased susceptibility to infections in cystic fibrosis and related diseases. As shown previously, the proinflammatory state is started by an IL-1b loop that is chronic in cystic fibrosis cells and induce excessive ROS production. The chronic oxidative stress might induce diverse cellular damages, including DNA mutations in the long term that might lead to disease (cancer, Alzheimer, etc.).
Perspectives
This work, and the related work shown below, are the result of near 3 decades of research in the intracellular signaling of CFTR in my laboratory. Now, all the previous results that appeared to look disconnected has been now shown to be closely related and, in the future, might explain many of the reasons for the complex cystic fibrosis phenotype. However, the chronic inflammation that induce the CFTR failure or the increased intracellular chloride might be responsible for many diseases in which CFTR and other chloride channels are involved, including asthma, COPD, Alzheimer, Parkinson and cancer. 1: Valdivieso ÁG, Clauzure M, Massip-Copiz MM, Cancio CE, Asensio CJA, Mori C, Santa-Coloma TA. Impairment of CFTR activity in cultured epithelial cells upregulates the expression and activity of LDH resulting in lactic acid hypersecretion. Cell Mol Life Sci. 2019 Jan 1. doi: 10.1007/s00018-018-3001-y. [Epub ahead of print] PubMed PMID: 30599064. 2: Massip-Copiz MM, Santa-Coloma TA. Extracellular pH and lung infections in cystic fibrosis. Eur J Cell Biol. 2018 Aug;97(6):402-410. doi: 10.1016/j.ejcb.2018.06.001. Epub 2018 Jun 18. Review. PubMed PMID: 29933921. 3: Valdivieso ÁG, Dugour AV, Sotomayor V, Clauzure M, Figueroa JM, Santa-Coloma TA. N-acetyl cysteine reverts the proinflammatory state induced by cigarette smoke extract in lung Calu-3 cells. Redox Biol. 2018 Jun;16:294-302. doi: 10.1016/j.redox.2018.03.006. Epub 2018 Mar 14. PubMed PMID: 29573703; PubMed Central PMCID: PMC5953002. 4: Massip-Copiz M, Clauzure M, Valdivieso ÁG, Santa-Coloma TA. Epiregulin (EREG) is upregulated through an IL-1β autocrine loop in Caco-2 epithelial cells with reduced CFTR function. J Cell Biochem. 2018 Mar;119(3):2911-2922. doi: 10.1002/jcb.26483. Epub 2017 Nov 24. PubMed PMID: 29091309. 5: Valdivieso ÁG, Mori C, Clauzure M, Massip-Copiz M, Santa-Coloma TA. CFTR modulates RPS27 gene expression using chloride anion as signaling effector. Arch Biochem Biophys. 2017 Nov 1;633:103-109. doi: 10.1016/j.abb.2017.09.014. Epub 2017 Sep 21. PubMed PMID: 28941802. 6: Massip-Copiz MM, Clauzure M, Valdivieso ÁG, Santa-Coloma TA. CFTR impairment upregulates c-Src activity through IL-1β autocrine signaling. Arch Biochem Biophys. 2017 Feb 15;616:1-12. doi: 10.1016/j.abb.2017.01.003. Epub 2017 Jan 11. PubMed PMID: 28088327. 7: Clauzure M, Valdivieso ÁG, Massip-Copiz MM, Mori C, Dugour AV, Figueroa JM, Santa-Coloma TA. Intracellular Chloride Concentration Changes Modulate IL-1β Expression and Secretion in Human Bronchial Epithelial Cultured Cells. J Cell Biochem. 2017 Aug;118(8):2131-2140. doi: 10.1002/jcb.25850. Epub 2017 Apr 18. PubMed PMID: 27996167. 8: Massip Copiz MM, Santa Coloma TA. c- Src and its role in cystic fibrosis. Eur J Cell Biol. 2016 Oct;95(10):401-413. doi: 10.1016/j.ejcb.2016.08.001. Epub 2016 Aug 11. Review. PubMed PMID: 27530912. 9: Valdivieso ÁG, Clauzure M, Massip-Copiz M, Santa-Coloma TA. The Chloride Anion Acts as a Second Messenger in Mammalian Cells - Modifying the Expression of Specific Genes. Cell Physiol Biochem. 2016;38(1):49-64. doi: 10.1159/000438608. Epub 2016 Jan 8. PubMed PMID: 26741366. 10: Clauzure M, Valdivieso AG, Massip Copiz MM, Schulman G, Teiber ML, Santa-Coloma TA. Disruption of interleukin-1β autocrine signaling rescues complex I activity and improves ROS levels in immortalized epithelial cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function. PLoS One. 2014 Jun 5;9(6):e99257. doi: 10.1371/journal.pone.0099257. eCollection 2014. PubMed PMID: 24901709; PubMed Central PMCID: PMC4047112. 11: Valdivieso AG, Santa-Coloma TA. CFTR activity and mitochondrial function. Redox Biol. 2013 Feb 5;1:190-202. doi: 10.1016/j.redox.2012.11.007. Review. PubMed PMID: 24024153; PubMed Central PMCID: PMC3757715. 12: Valdivieso AG, Clauzure M, Marín MC, Taminelli GL, Massip Copiz MM, Sánchez F, Schulman G, Teiber ML, Santa-Coloma TA. The mitochondrial complex I activity is reduced in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function. PLoS One. 2012;7(11):e48059. doi: 10.1371/journal.pone.0048059. Epub 2012 Nov 21. PubMed PMID: 23185247; PubMed Central PMCID: PMC3504030. 13: Valdivieso ÁG, Marín MC, Clauzure M, Santa-Coloma TA. Measurement of cystic fibrosis transmembrane conductance regulator activity using fluorescence spectrophotometry. Anal Biochem. 2011 Nov 15;418(2):231-7. doi: 10.1016/j.ab.2011.07.029. Epub 2011 Jul 30. PubMed PMID: 21864494. 14: Taminelli GL, Sotomayor V, Valdivieso AG, Teiber ML, Marín MC, Santa-Coloma TA. CISD1 codifies a mitochondrial protein upregulated by the CFTR channel. Biochem Biophys Res Commun. 2008 Jan 25;365(4):856-62. Epub 2007 Nov 29. PubMed PMID: 18047834. 15: Valdivieso AG, Marcucci F, Taminelli G, Guerrico AG, Alvarez S, Teiber ML, Dankert MA, Santa-Coloma TA. The expression of the mitochondrial gene MT-ND4 is downregulated in cystic fibrosis. Biochem Biophys Res Commun. 2007 May 11;356(3):805-9. Epub 2007 Mar 19. PubMed PMID: 17382898. 16: González-Guerrico AM, Cafferata EG, Radrizzani M, Marcucci F, Gruenert D, Pivetta OH, Favaloro RR, Laguens R, Perrone SV, Gallo GC, Santa-Coloma TA. Tyrosine kinase c-Src constitutes a bridge between cystic fibrosis transmembrane regulator channel failure and MUC1 overexpression in cystic fibrosis. J Biol Chem. 2002 May 10;277(19):17239-47. Epub 2002 Feb 28. PubMed PMID: 11872746. 17: Cafferata EG, Guerrico AM, Pivetta OH, Santa-Coloma TA. NF-kappaB activation is involved in regulation of cystic fibrosis transmembrane conductance regulator (CFTR) by interleukin-1beta. J Biol Chem. 2001 May 4;276(18):15441-4. Epub 2001 Feb 5. PubMed PMID: 11278608. 18: Cafferata EG, González-Guerrico AM, Giordano L, Pivetta OH, Santa-Coloma TA. Interleukin-1beta regulates CFTR expression in human intestinal T84 cells. Biochim Biophys Acta. 2000 Feb 21;1500(2):241-8. PubMed PMID: 10657593. 19: Cafferata EG, Gonzalez-Guerrico AM, Pivetta OH, Santa-Coloma TA. Identification by differential display of a mRNA specifically induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in T84 human colon carcinoma cells. Cell Mol Biol (Noisy-le-grand). 1996 Jul;42(5):797-804. PubMed PMID: 8832110.
Dr Tomás A. Santa Coloma
Institute for Biomedical Research (BIOMED), CONICET, UCA
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This page is a summary of: Impairment of CFTR activity in cultured epithelial cells upregulates the expression and activity of LDH resulting in lactic acid hypersecretion, Cellular and Molecular Life Sciences, January 2019, Springer Science + Business Media,
DOI: 10.1007/s00018-018-3001-y.
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