Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival.
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.
Kang
Sang Soo
SS
Center for Neural Science, Future Fusion Technology Laboratory, Seoul National University, Seoul, Republic of Korea.
Han
Kyung-Seok
KS
Ku
Bo Mi
BM
Lee
Yeon Kyung
YK
Hong
Jinpyo
J
Shin
Hye Young
HY
Almonte
Antoine G
AG
Woo
Dong Ho
DH
Brat
Daniel J
DJ
Hwang
Eun Mi
EM
Yoo
Seung Hyun
SH
Chung
Chun Kee
CK
Park
Sung-Hye
SH
Paek
Sun Ha
SH
Roh
Eun Joo
EJ
Lee
Sung Joong
SJ
Park
Jae-Yong
JY
Traynelis
Stephen F
SF
Lee
C Justin
CJ
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
D000697:Central Nervous System Stimulants; D053496:Inositol 1,4,5-Trisphosphate Receptors; D002110:Caffeine; D002118:Calcium