LRRC8A (Leucine Rich Repeat Containing 8 VRAC Subunit A)

RNA interference-mediated downregulation of LRRC8A reduces proliferation in patient-derived GBM cell cultures, suggesting that VRACs promote cancer cell growth. LRRC8A/VRAC-mediated effects on cell proliferation are driven by a mechanism involving the chloride-sensitive protein kinase WNK1, mTOR complex 2 and activation of downstream kinases AKT and SGK.

Thus, GATOR1 not only participates in the cellular response to amino acid availability but also plays a role in resistance to DNA-damaging anticancer drugs. This novel function of GATOR1 should be taken into account when developing new strategies to combat chemoresistance.

This review provides a comprehensive overview of the regulatory mechanisms of LRRC8A in these pathologies. The primary goal was to assess the potential of LRRC8A as a therapeutic target for treating diseases and address key unresolved issues.

Disruption of any of the non-essential subunits, LRRC8B-LRRC8E, had no discernible effect on T or B cell development in mice. Whereas tumor-produced cGAMP markedly suppresses tumor growth, transport of this immunomodulator to the tumor environment primarily involves transporters distinct from VRAC.

The function of knockout aortic and mesenteric vessels was less impaired by Ang II, as reflected by less augmented contraction to norepinephrine and serotonin and preserved relaxation to acetylcholine and sodium nitroprusside...Ang II caused less proliferation (lower PCNA [proliferating cell nuclear antigen]) and less induction of senescence in knockout vessels. LRRC8A anion channels support VSMC inflammation and the associated vascular dysfunction, which impairs BP dipping in hypertension.

Furthermore, we mimicked the absence of the neutralizing acetyl moiety that is observed after loss of NAA60 by introducing positively charged amino acids at the N-termini of LRRC8A/D, which indeed decreased cis- and carboplatin sensitivity. Our findings highlight the importance of N-terminal acetylation by NAA60 for effective platinum drug uptake, offering new insights into overcoming drug resistance.

Additionally, the WNK1-AMPK pathway was, at least in part, involved in the high [K+]e-induced upregulation of CCL2. Collectively, modulating KCa3.1 and LRRC8A activities offers a promising strategy to suppress CCL2 secretion in TAMs, potentially limiting the CCL2-induced infiltration of immunosuppressive cells (TAMs, Tregs, and MDSCs) in the TME.

Inhibition of the extracellular hydroxylases CD39 and ENPP1 maintains extracellular ATP and cGAMP, which promotes VRAC-enhanced CD8 T cell anticancer function. Thus, the transfer of cGAMP to T cells by VRACs may be a strategy that can be targeted in future cancer therapies.

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.

These findings establish the new mTORC2-centric axis for VRAC dependent regulation of cellular functions and uncover potential targets for GBM intervention. Cell biologyMolecular biologyCancer.

In the nude mouse xenograft model, LRRC8A knockdown suppressed the tumorigenesis of subcutaneously implanted breast cancer cells. These results suggest that abundantly expressed VRACs are a conduit of ATP release in undifferentiated cells, including cancer cells.

Strikingly, all of the 9 genes, including LRRC8A, the same as PRMT5, were associated with poor prognosis in LUAD. Our research highlights the potential of PRMT5 as a novel prognostic biomarker and its relationship with IC genes in LC.