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

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

研究成果: Article査読

4 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)202-211
ページ数10
ジャーナルMolecular Oncology
13
2
DOI
出版ステータスPublished - 2019 2

ASJC Scopus subject areas

  • 分子医療
  • 遺伝学
  • 腫瘍学
  • 癌研究

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