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Ibarra C, Karlsson M, Codeluppi S, Varas-Godoy M, Zhang S, Louhivuori L, Mangsbo S, Hosseini A, Soltani N, Kaba R, Kalle Lundgren T, Hosseini A, Tanaka N, Oya M, Wiklund P, Miyakawa A, Uhlén P
Mol Oncol 13 (2) 202-211 [2019-02-00; online 2018-12-13]
Bacillus Calmette-Guérin (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-κB) 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.
PubMed 30358081
DOI 10.1002/1878-0261.12397
Crossref 10.1002/1878-0261.12397