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

Bin Liu; Ran Chen; Yidan Zhang; Jinrong Huang; Yonglun Luo; Susanne Rosthøj; Chenyang Zhao; Marja Jäättelä

doi:10.1016/j.celrep.2023.112137

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

Bin Liu^*
, Ran Chen
, Yidan Zhang
, Jinrong Huang
, Yonglun Luo
, Susanne Rosthøj
, Chenyang Zhao
, Marja Jäättelä

^*Corresponding author af dette arbejde

Institut for Biomedicin - Forskning og uddannelse, Skou-bygningen

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

11 Citationer (Scopus)

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 Ca 2+ 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.

Originalsprog	Engelsk
Artikelnummer	112137
Tidsskrift	Cell Reports
Vol/bind	42
Nummer	2
Antal sider	20
ISSN	2211-1247
DOI	https://doi.org/10.1016/j.celrep.2023.112137
Status	Udgivet - 28 feb. 2023

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@article{14d0953d35484002b58b58ba803cb2bc,

title = "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 Ca 2+ 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. ",

keywords = "CP: Cancer, P2RX4, STAT3, antihistamine, apoptosis, drug repurposing, lysosome, pH regulation",

author = "Bin Liu and Ran Chen and Yidan Zhang and Jinrong Huang and Yonglun Luo and Susanne Rosth{\o}j and Chenyang Zhao and Marja J{\"a}{\"a}ttel{\"a}",

year = "2023",

month = feb,

day = "28",

doi = "10.1016/j.celrep.2023.112137",

language = "English",

volume = "42",

journal = "Cell Reports",

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TY - JOUR

T1 - Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux

AU - Liu, Bin

AU - Chen, Ran

AU - Zhang, Yidan

AU - Huang, Jinrong

AU - Luo, Yonglun

AU - Rosthøj, Susanne

AU - Zhao, Chenyang

AU - Jäättelä, Marja

PY - 2023/2/28

Y1 - 2023/2/28

N2 - 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 Ca 2+ 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.

AB - 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 Ca 2+ 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.

KW - CP: Cancer

KW - P2RX4

KW - STAT3

KW - antihistamine

KW - apoptosis

KW - drug repurposing

KW - lysosome

KW - pH regulation

UR - https://www.scopus.com/pages/publications/85148370432

U2 - 10.1016/j.celrep.2023.112137

DO - 10.1016/j.celrep.2023.112137

M3 - Journal article

C2 - 36807142

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 2

M1 - 112137

ER -