title: Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.
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 Ca(2+) signaling, we identified caffeine as an inhibitor of glioblastoma cell motility. Caffeine, which is known to activate ryanodine receptors, paradoxically inhibits Ca(2+) increase by inositol 1,4,5-trisphospate receptor subtype 3 (IP(3)R3), the expression of which is increased in glioblastoma cells. Consequently, by inhibiting IP(3)R3-mediated Ca(2+) 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 IP(3)R3 as a novel therapeutic target and identify caffeine as a possible adjunct therapy to slow invasive growth of glioblastoma.
authors.affiliation: Center for Neural Science, Future Fusion Technology Laboratory, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.forename: Kyung-Seok
authors.initials: KS
authors.lastname: Han
authors.forename: Bo Mi
authors.initials: BM
authors.lastname: Ku
authors.forename: Yeon Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Jinpyo
authors.initials: J
authors.lastname: Hong
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Shin
authors.forename: Antoine G
authors.initials: AG
authors.lastname: Almonte
authors.forename: Dong Ho
authors.initials: DH
authors.lastname: Woo
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Hwang
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Yoo
authors.forename: Chun Kee
authors.initials: CK
authors.lastname: Chung
authors.forename: Sung-Hye
authors.initials: SH
authors.lastname: Park
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Paek
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Roh
authors.forename: Sung Joong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Park
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.forename: C Justin
authors.initials: CJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000697:Central Nervous System Stimulants; D053496:Inositol 1,4,5-Trisphosphate Receptors; D002110:Caffeine; D002118:Calcium