title: Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R.
abstract: Calcium (Ca2+) signaling is an important signaling process, implicated in cancer cell proliferation and motility of the deadly glioblastomas that aggressively invade neighboring brain tissue. We have previously demonstrated that caffeine blocks glioblastoma invasion and extends survival by inhibiting Ca2+release channel inositol 1,4,5-trisphosphate receptor (IP3R) subtype 3. Trifluoperazine (TFP) is an FDA-approved antipsychotic drug for schizophrenia. Interestingly, TFP has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma, and T-cell lymphoma. However, the possible anticancer effect of TFP on glioblastoma has not been tested. Here, we report that TFP potently suppresses proliferation, motility, and invasion of glioblastoma cells in vitro, and tumor growth in in vivo xenograft mouse model. Unlike caffeine, TFP triggers massive and irreversible release of Ca2+from intracellular stores by IP3R subtype 1 and 2 by directly interacting at the TFP-binding site of a Ca2+-binding protein, calmodulin subtype 2 (CaM2). TFP binding to CaM2 causes a dissociation of CaM2 from IP3R and subsequent opening of IP3R. Compared with the control neural stem cells, various glioblastoma cell lines showed enhanced expression of CaM2 and thus enhanced sensitivity to TFP. On the basis of these findings, we propose TFP as a potential therapeutic drug for glioblastoma by aberrantly and irreversibly increasing Ca2+in glioblastoma cells. Mol Cancer Ther; 16(1); 217-27. ©2016 AACR.
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Seokmin
authors.initials: S
authors.lastname: Kang
authors.affiliation: Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Jinpyo
authors.initials: J
authors.lastname: Hong
authors.affiliation: Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.|KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
authors.forename: Jung Moo
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyo Eun
authors.initials: HE
authors.lastname: Moon
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Borami
authors.initials: B
authors.lastname: Jeon
authors.affiliation: Gyeongnam Department of Environmental Toxicology and Chemistry, Korea Institute of Toxicology, Jinju, Republic of Korea.
authors.forename: Jungil
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Nal Ae
authors.initials: NA
authors.lastname: Yoon
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Paek
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Roh
authors.affiliation: Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea. Kangss@gnu.ac.kr cjl@kist.re.kr.|KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.|Neuroscience Program, University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: C Justin
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, Republic of Korea. Kangss@gnu.ac.kr cjl@kist.re.kr.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D011485:Protein Binding; D014268:Trifluoperazine / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002147:Calmodulin; D053496:Inositol 1,4,5-Trisphosphate Receptors; D014268:Trifluoperazine; D002118:Calcium