Epidermal growth factor receptor activity upregulates lactate dehydrogenase A expression, lactate dehydrogenase activity, and lactate secretion in cultured IB3-1 cystic fibrosis lung epithelial cells

MASSIP-COPIZ, MARÍA MACARENA; VALDIVIESO, ÁNGEL G.; CLAUZURE, MARIÁNGELES; MORI, CONSUELO; ASENSIO, CRISTIAN J.A.; AGUILAR, MARÍA Á.; SANTA-COLOMA, TOMÁS A.

BIOCHEMISTRY AND CELL BIOLOGY

NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS

Año: 2021 p. 1 - 12

0829-8211

Cystic fibrosis (CF) is caused by mutations in the CFTR gene. It has been postulated that a reducedHCO3− transport in CF through CFTR may lead to a decreased airway surface liquid (ASL) pH. Incontrast, others have reported no changes in the extracellular pH (pHe). We have recently reportedthat in carcinoma Caco-2/pRS26 cells (shRNA for CFTR) or CF lung epithelial IB3-1 cells, theCFTR failure decreased mitochondrial Complex I activity due to an autocrine IL1B loop, andincreased lactic acid production. The secreted lactate accounted for the reduced pHe since oxamatefully restored the pHe. These effects were attributed to the IL-1β autocrine loop and the downstreamsignaling kinases c-Src and JNK. Here we show that the pHe of IB3-1 cells can be restored to normalpHe values (~7.4) by incubation with the epidermal growth factor receptor (EGFR, HER1, ErbB1)inhibitors AG1478 or PD168393. The inhibitor PD168393, fully restored the pHe values of IB3-1cells, suggesting that the reduced pHe is mainly due to the increased EGFR activity and lactate. Also,in IB3-1 CF cells, the LDHA mRNA, protein expression, and activity are down-regulated underEGFR inhibition. Thus, a constitutive EGFR activation seems to be responsible for the reduced pHein IB3-1 CF cells.