LRRC8A/PKC/FLNA pathway activation is detrimental to colon cancer patients.

Abstract

The volume-regulated anion channel (VRAC) is implicated in remodeling the cytoskeleton. Leucine-rich repeat-containing 8A (LRRC8A) serves as a critical constituent of VRAC; however, its interaction with the scaffolding protein FLNA has not yet been clearly defined. This study demonstrated that the expression levels of the FLNA protein in colon cancer tissues exceeded those in the corresponding adjacent non-cancerous tissues, and its elevated mRNA expression was associated with an unfavorable prognosis in colon cancer patients. Transcriptomic analysis indicated that FLNA silencing altered the expression of 838 genes in HCT116 cells, primarily related to cellular motility and growth. Upon silencing FLNA in HCT116 and SW480 cells, cell migration and proliferation were markedly diminished, the cell cycle experienced a G2/M phase arrest, and apoptosis rates significantly increased. The Pearson correlation coefficient for genetic distances between FLNA and LRRC8A across various species was calculated at 0.912. At the transcription level, the correlation coefficient between LRRC8A and FLNA was determined to be 0.547, with colon cancer patients exhibiting elevated levels of both FLNA and LRRC8A mRNA showing the most adverse outcomes. Immunofluorescence analysis revealed a high Pearson's co-localization coefficient between PKC and FLNA proteins. Treatment of HCT116 cells with 20 μM DCPIB resulted in the reorganization and dispersion of aggregated FLNA proteins, coinciding with a notable reduction in the concentrations of DAG and PKC. In summary, LRRC8A modulates FLNA to influence cellular growth and migration through the DAG-PKC signaling pathway, and their combination could signify a prospective biomarker for colon cancer.