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BCG-induced cytokine release in bladder cancer cells is regulated by Ca2+ signaling
Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden.
Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden.
Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden;Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden;Univ Los Andes, Ctr Invest Biomed, Fac Med, Santiago, Chile.
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2019 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, no 2, p. 202-211Article in journal (Refereed) Published
Abstract [en]

Bacillus Calmette-Guerin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 13, no 2, p. 202-211
Keywords [en]
BCG, calcium signaling, TLR4, urinary bladder cancer
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:uu:diva-377672DOI: 10.1002/1878-0261.12397ISI: 000457747900006PubMedID: 30358081OAI: oai:DiVA.org:uu-377672DiVA, id: diva2:1291528
Funder
Swedish Research Council, 20093364Swedish Research Council, 2013-3189Swedish Research Council, 2017-00815Knut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Swedish Cancer Society, CAN 2013-802Swedish Cancer Society, CAN 2016-801Åke Wiberg FoundationMagnus Bergvall FoundationStiftelsen Olle Engkvist ByggmästareSwedish Society for Medical Research (SSMF)Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved

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Mangsbo, Sara

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