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

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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+ efflux sensitizes cancer cells to apoptosis induced by STAT3 inhibition and acts synergistically with STAT3 inhibition in restricting the tumor growth of A549 non-small cell lung carcinoma xenografts. These findings identify lysosomal H+ efflux and STAT3 inhibition as anticancer mechanisms of CADs and reinforce the repurposing of safe and inexpensive CADs as cancer drugs with a drug combination strategy.
OriginalsprogEngelsk
Artikelnummer112137
TidsskriftCell Reports
Vol/bind42
Udgave nummer2
Antal sider20
ISSN2211-1247
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank Dr. Dmitry Malkov for providing valuable reagents and Louise Vanderfox and Tiina Naumanen Dietrich for technical assistance. The research reported in this publication was supported by European Research Council ( AdG 340751 to M.J.), Danish National Research Foundation ( DNRF125 to M.J.), Danish Cancer Society ( R167-A11061 and R269-A15695 to M.J.), Danish Council for Independent Research ( DFF-7016-00360 to M.J.), and Novo Nordisk Foundation ( NNF15OC0016914 to M.J.).

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© 2023 The Authors

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