BCG-induced cytokine release in bladder cancer cells is regulated by Ca2+ signaling

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+ 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 pro-inflammatory 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.

Molecular oncology. 2018 Oct 25 [Epub ahead of print]

Cristián Ibarra, Marie Karlsson, Simone Codeluppi, Manuel Varas-Godoy, Songbai Zhang, Lauri Louhivuori, Sara Mangsbo, Arad Hosseini, Navid Soltani, Rahim Kaba, T Kalle Lundgren, Abolfazl Hosseini, Nobuyuki Tanaka, Mototsugu Oya, Peter Wiklund, Ayako Miyakawa, Per Uhlén

Department of Medical Biochemistry and Biophysics., Department of Pharmaceutical Biosciences, Science for Life laboratory, Uppsala University, Uppsala, Sweden., Department of Molecular Medicine and Surgery, Karolinska University Hospital, SE-171 76, Stockholm, Sweden., Department of Urology, Keio University School of Medicine, 160-8582, Tokyo, Japan.