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Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is crucial to driving malignant progression and predicting poor prognosis of multiple human cancers, including bladder cancer, making STAT3 a promising target of cancer therapeutics. Cryptotanshinone (CTS) is an anticancer ingredient of Danshen (<jats:styled-content style=\"fixed-case\">\n<jats:italic>Salvia miltiorrhiza<\/jats:italic>\n<\/jats:styled-content>), a top\u2010graded Chinese medicinal herb. However, whether CTS targets STAT3 to exert its cytotoxic effect on human bladder cancer remains unknown. Herein, we demonstrated that CTS is cytotoxic to multiple human urinary bladder transitional cell carcinoma (TCC) cell lines while sparing normal human urothelial cells. CTS provoked apoptosis\u2010dependent bladder TCC cytotoxicity, as apoptosis blockage by z\u2010VAD\u2010fmk markedly rescued the clonogenicity of CTS\u2010treated cells. Besides, CTS was found to suppress constitutive and interleukin 6\u2010inducible activation of STAT3, evidenced by the downregulation of STAT3 tyrosine 705 phosphorylation and BCL2, a recognized STAT3 transcriptional target. Notably, ectopic expression of a dominant\u2010active STAT3 mutant (STAT3\u2010C) or BCL\u20102 alleviated CTS\u2010induced apoptosis and clonogenicity inhibition, thus confirming STAT3 blockade as a pivotal mechanism of CTS's cytotoxic action on bladder TCC cells. Lastly, immunoblotting revealed that CTS lowered the levels of active JAK2, an upstream kinase that mediates STAT3 tyrosine 705 phosphorylation. Altogether, we conclude that the blockade of the JAK2\/STAT3\/BCL\u20102 antiapoptotic signaling axis is a vital mechanism whereby CTS provokes bladder cancer cytotoxicity. The current evidence implicates CTS's potential to be translated into a bladder cancer therapeutic agent.<\/jats:p>","DOI":"10.1002\/tox.24446","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:15:16Z","timestamp":1732709716000},"page":"624-635","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cryptotanshinone Suppresses the <scp>STAT3<\/scp>\/<scp>BCL<\/scp>\u20102 Pathway to Provoke Human Bladder Urothelial Carcinoma Cell Death"],"prefix":"10.1002","volume":"40","author":[{"given":"Min\u2010Che","family":"Tung","sequence":"first","affiliation":[{"name":"Division of Urology, Department of Surgery Tungs' Taichung MetroHarbor Hospital  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ge\u2010Man","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen\u2010Chyi","family":"Dai","sequence":"additional","affiliation":[{"name":"Doctoral Program in Biotechnology Industrial Innovation and Management National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen\u2010Hsuan","family":"Hsu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsiang\u2010Chun","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Life Sciences National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei\u2010Ting","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Life Sciences National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yann\u2010Jen","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Life Sciences National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien\u2010Hsing","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Taichung Veterans General Hospital  Taichung Taiwan"},{"name":"Doctoral Program in Translational Medicine National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi\u2010Hsin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Taichung Tzu Chi Hospital Buddhist Tzu chi Medical Foundation  Taichung Taiwan"},{"name":"School of Medicine Tzu Chi University  Hualein Taiwan"},{"name":"Department of Artificial Intelligence and Data Science National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3509-3713","authenticated-orcid":false,"given":"Chia\u2010Che","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences National Chung Hsing University  Taichung Taiwan"},{"name":"Doctoral Program in Biotechnology Industrial Innovation and Management National Chung Hsing University  Taichung Taiwan"},{"name":"Department of Life Sciences National Chung Hsing University  Taichung Taiwan"},{"name":"Doctoral Program in Translational Medicine National Chung Hsing University  Taichung Taiwan"},{"name":"Master Program in Precision Health, Rong Hsing Research Center for Translational Medicine, The iEGG and Animal Biotechnology Research Center National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.7189\/jogh.13.04109"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2021.08.010"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30512-8"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12645-023-00221-7"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2016.06.020"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21631"},{"issue":"6","key":"e_1_2_12_8_1","article-title":"Immune Checkpoint Inhibitors as a Treatment Option for Bladder Cancer: Current Evidence","volume":"15","author":"Okobi T. 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