Cationic amphiphilic antihistamines inhibit STAT3 via Ca²⁺-dependent lysosomal H⁺ efflux.

ABSTRACT: Commonly used antihistamines and other cationic amphiphilic drugs (CADs) are emerging as putative cancer drugs. Their unique chemical structure enables CADs to accumulate rapidly inside lysosomes, where they increase lysosomal pH, alter lysosomal lipid metabolism, and eventually cause lysosomal membrane permeabilization. Here, we show that CAD-induced rapid elevation in lysosomal pH is caused by a lysosomal H⁺ efflux that requires P2RX4-mediated lysosomal Ca²⁺ release and precedes the lysosomal membrane permeabilization. The subsequent cytosolic acidification triggers the dephosphorylation, lysosomal translocation, and inactivation of the oncogenic signal transducer and activator of transcription 3 (STAT3) transcription factor. Moreover, CAD-induced lysosomal H^+<

SUBMITTER: Liu B 

PROVIDER: S-EPMC9989825 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature