Trifluoperazine, a well-known antipsychotic, inhibits glioblastoma invasion by binding to calmodulin and disinhibiting calcium release channel IP3R

Seokmin Kang, Jinpyo Hong, Jung Moo Lee, Hyo Eun Moon, Borami Jeon, Jungil Choi, Nal Ae Yoon, Sun Ha Paek, Eun Joo Roh, Changjoon Lee, Sang Soo Kang

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)217-227
Number of pages11
JournalMolecular Cancer Therapeutics
Volume16
Issue number1
DOIs
Publication statusPublished - 2017 Jan 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kang, S., Hong, J., Lee, J. M., Moon, H. E., Jeon, B., Choi, J., Yoon, N. A., Paek, S. H., Roh, E. J., Lee, C., & Kang, S. S. (2017). Trifluoperazine, a well-known antipsychotic, inhibits glioblastoma invasion by binding to calmodulin and disinhibiting calcium release channel IP3R. Molecular Cancer Therapeutics, 16(1), 217-227. https://doi.org/10.1158/1535-7163.MCT-16-0169-T