Supplementary Methods from Caffeine-Mediated Inhibition of Calcium Release Channel Inositol 1,4,5-Trisphosphate Receptor Subtype 3 Blocks Glioblastoma Invasion and Extends Survival

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

doi:10.1158/0008-5472.22385762.v1

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Supplementary Methods from Caffeine-Mediated Inhibition of Calcium Release Channel Inositol 1,4,5-Trisphosphate Receptor Subtype 3 Blocks Glioblastoma Invasion and Extends Survival

journal contribution

posted on 2023-03-30, 20:01 authored by 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

Supplementary Methods from Caffeine-Mediated Inhibition of Calcium Release Channel Inositol 1,4,5-Trisphosphate Receptor Subtype 3 Blocks Glioblastoma Invasion and Extends Survival

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ARTICLE 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 Ca2+ 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 IP3R3-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. Cancer Res; 70(3); 1173–83