EGFR activity upregulates lactate dehydrogenase A (LDHA) expression, LDH activity and lactate secretion in cultured IB3-1 cystic fibrosis lung epithelial cells.

EGFR activity upregulates lactate dehydrogenase A (LDHA) expression, LDH activity and lactate secretion in cultured IB3-1 cystic fibrosis lung epithelial cells. Biochem Cell Biol. 2021 Jan 22;: Authors: Massip-Copiz MM, Valdivieso ÁG, Clauzure M, Mori C, Asensio CJA, Aguilar MÁ, Santa-Coloma T Abstract Cystic fibrosis (CF) is caused by mutations in the CFTR gene. It has been postulated that a reduced HCO3- transport in CF through CFTR may lead to a decreased airway surface liquid (ASL) pH. In contrast, others have reported no changes in the extracellular pH (pHe). We have recently reported that in carcinoma Caco-2/pRS26 cells (shRNA for CFTR) or CF lung epithelial IB3-1 cells, the CFTR failure decreased mitochondrial Complex I activity due to an autocrine IL1B loop, and increased lactic acid production. The secreted lactate accounted for the reduced pHe since oxamate fully restored the pHe. These effects were attributed to the IL-1β autocrine loop and the downstream signaling kinases c-Src and JNK. Here we show that the pHe of IB3-1 cells can be restored to normal pHe 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 IB3-1 cells, 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-regula...
Source: Biochemistry and Cell Biology - Category: Biochemistry Authors: Tags: Biochem Cell Biol Source Type: research