Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux
Summary: 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 lysos...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723001481 |
| _version_ | 1797903499917262848 |
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| author | Bin Liu Ran Chen Yidan Zhang Jinrong Huang Yonglun Luo Susanne Rosthøj Chenyang Zhao Marja Jäättelä |
| author_facet | Bin Liu Ran Chen Yidan Zhang Jinrong Huang Yonglun Luo Susanne Rosthøj Chenyang Zhao Marja Jäättelä |
| author_sort | Bin Liu |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-10T09:33:58Z |
| format | Article |
| id | doaj.art-2705740b6b6f4b9da72f3ff64cef9201 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-10T09:33:58Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2705740b6b6f4b9da72f3ff64cef92012023-02-18T04:16:48ZengElsevierCell Reports2211-12472023-02-01422112137Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ effluxBin Liu0Ran Chen1Yidan Zhang2Jinrong Huang3Yonglun Luo4Susanne Rosthøj5Chenyang Zhao6Marja Jäättelä7Cell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), 2100 Copenhagen, Denmark; Corresponding authorCell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), 2100 Copenhagen, DenmarkSchool of Medicine and Pharmacy, Ocean University of China, Qingdao 266555, ChinaBGI-Shenzhen, Shenzhen 518083, China; Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark; Lars Bolund Institute of Regenerative Medicine, Qingdao-Europe Advanced Institute for Life Sciences, BGI-Qingdao, Qingdao 266555, ChinaBGI-Shenzhen, Shenzhen 518083, China; Lars Bolund Institute of Regenerative Medicine, Qingdao-Europe Advanced Institute for Life Sciences, BGI-Qingdao, Qingdao 266555, China; Department of Biomedicine, Aarhus University, 8000 Aarhus, DenmarkStatistics and Data Analysis, Danish Cancer Society Research Center, Copenhagen, DenmarkSchool of Medicine and Pharmacy, Ocean University of China, Qingdao 266555, ChinaCell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), 2100 Copenhagen, Denmark; Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723001481CP: Cancer |
| spellingShingle | Bin Liu Ran Chen Yidan Zhang Jinrong Huang Yonglun Luo Susanne Rosthøj Chenyang Zhao Marja Jäättelä Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux Cell Reports CP: Cancer |
| title | Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux |
| title_full | Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux |
| title_fullStr | Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux |
| title_full_unstemmed | Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux |
| title_short | Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux |
| title_sort | cationic amphiphilic antihistamines inhibit stat3 via ca2 dependent lysosomal h efflux |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723001481 |
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