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

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Standard

Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux. / Liu, Bin; Chen, Ran; Zhang, Yidan; Huang, Jinrong; Luo, Yonglun; Rosthøj, Susanne; Zhao, Chenyang; Jäättelä, Marja.

I: Cell Reports, Bind 42, Nr. 2, 112137, 2023.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Liu, B, Chen, R, Zhang, Y, Huang, J, Luo, Y, Rosthøj, S, Zhao, C & Jäättelä, M 2023, 'Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux', Cell Reports, bind 42, nr. 2, 112137. https://doi.org/10.1016/j.celrep.2023.112137

APA

Liu, B., Chen, R., Zhang, Y., Huang, J., Luo, Y., Rosthøj, S., Zhao, C., & Jäättelä, M. (2023). Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux. Cell Reports, 42(2), [112137]. https://doi.org/10.1016/j.celrep.2023.112137

Vancouver

Liu B, Chen R, Zhang Y, Huang J, Luo Y, Rosthøj S o.a. Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux. Cell Reports. 2023;42(2). 112137. https://doi.org/10.1016/j.celrep.2023.112137

Author

Liu, Bin ; Chen, Ran ; Zhang, Yidan ; Huang, Jinrong ; Luo, Yonglun ; Rosthøj, Susanne ; Zhao, Chenyang ; Jäättelä, Marja. / Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux. I: Cell Reports. 2023 ; Bind 42, Nr. 2.

Bibtex

@article{850b6cc75c5443c9b35b3fd1d4d158ee,
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 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.",
keywords = "antihistamine, apoptosis, CP: Cancer, drug repurposing, lysosome, P2RX4, pH regulation, STAT3",
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}",
note = "Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
doi = "10.1016/j.celrep.2023.112137",
language = "English",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",

}

RIS

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

N1 - Publisher Copyright: © 2023 The Authors

PY - 2023

Y1 - 2023

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 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.

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 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.

KW - antihistamine

KW - apoptosis

KW - CP: Cancer

KW - drug repurposing

KW - lysosome

KW - P2RX4

KW - pH regulation

KW - STAT3

U2 - 10.1016/j.celrep.2023.112137

DO - 10.1016/j.celrep.2023.112137

M3 - Journal article

C2 - 36807142

AN - SCOPUS:85148370432

VL - 42

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 2

M1 - 112137

ER -

ID: 337575503