Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival

Sang Soo Kang, Kyung Seok Han, Bo Mi Ku, Yeon Kyung Lee, Jinpyo Hong, Hye Young Shin, Antoine G. Almonte, Dong Ho Woo, Daniel J. Brat, Eun Mi Hwang, Seung Hyun Yoo, Chun Kee Chung, Sung Hye Park, Sun Ha Paek, Eun Joo Roh, Sung Joong Lee, Jae Yong Park, Stephen F. Traynelis, C. Justin Lee

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Calcium signaling is important in many signaling processes in cancer cell proliferation and motility including in deadly glioblastomas of the brain that aggressively invade neighboring tissue. We hypothesized that disturbing Ca 2+ signaling pathways might decrease the invasive behavior of giloblastoma, extending survival. Evaluating a panel of small-molecule modulators of Ca2+ signaling, we identified caffeine as an inhibitor of glioblastoma cell motility. Caffeine, which is known to activate ryanodine receptors, paradoxically inhibits Ca2+ increase by inositol 1,4,5-trisphospate receptor subtype 3 (IP3R3), the expression of which is increased in glioblastoma cells. Consequently, by inhibiting IP 3R3-mediated Ca2+ release, caffeine inhibited migration of glioblastoma cells in various in vitro assays. Consistent with these effects, caffeine greatly increased mean survival in a mouse xenograft model of glioblastoma. These findings suggest IP3R3 as a novel therapeutic target and identify caffeine as a possible adjunct therapy to slow invasive growth of glioblastoma.

Original languageEnglish
Pages (from-to)1173-1183
Number of pages11
JournalCancer Research
Volume70
Issue number3
DOIs
Publication statusPublished - 2010 Feb 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kang, S. S., Han, K. S., Ku, B. M., Lee, Y. K., Hong, J., Shin, H. Y., Almonte, A. G., Woo, D. H., Brat, D. J., Hwang, E. M., Yoo, S. H., Chung, C. K., Park, S. H., Paek, S. H., Roh, E. J., Lee, S. J., Park, J. Y., Traynelis, S. F., & Lee, C. J. (2010). Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival. Cancer Research, 70(3), 1173-1183. https://doi.org/10.1158/0008-5472.CAN-09-2886