BCG‐induced cytokine release in bladder cancer cells is regulated by Ca 2+ signaling

Autor: Per Uhlén, T. Kalle Lundgren, Sara M. Mangsbo, Rahim Kaba, Abolfazl Hosseini, Simone Codeluppi, Arad Hosseini, Marie Karlsson, Mototsugu Oya, Manuel Varas-Godoy, Peter Wiklund, Lauri Louhivuori, Ayako Miyakawa, Nobuyuki Tanaka, Navid Soltani, Cristian Ibarra, Songbai Zhang
Rok vydání: 2018
Předmět:
Zdroj: Molecular Oncology
Molecular Oncology, Vol 13, Iss 2, Pp 202-211 (2019)
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.12397
Popis: 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.
Databáze: OpenAIRE
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