PK 11195 differentially affects cell survival in human wild-type and 18 kDa translocator protein-silenced ADF astrocytoma cells.
Gliomas are the most common brain tumours with a poor prognosis due to their aggressiveness and propensity for recurrence. The 18 kDa translocator protein (TSPO) has been demonstrated to be greatly expressed in glioma cells and its over-expression has been correlated with glioma malignance grades. Due to both its high density in tumours and the pro-apoptotic activity of its ligands, TSPO has been suggested as a promising target in gliomas. With the aim to evidence if the TSPO expression level alters glioma cell susceptibility to undergo to cell death, we analysed the effects of the specific TSPO ligand, PK 11195, in human astrocytoma wild-type and TSPO-silenced cell lines. As first step, TSPO was characterised in human astrocytoma cell line (ADF). Our data demonstrated the presence of a single class of TSPO binding sites highly expressed in mitochondria. PK 11195 cell treatment activated an autophagic pathway followed by apoptosis mediated by the modulation of the mitochondrial permeability transition. In TSPO-silenced cells, produced by siRNA technique, a reduced cell proliferation rate and a decreased cell susceptibility to the PK 11195-induced anti-proliferative effect and mitochondrial potential dissipation were demonstrated respect to control cells. In conclusion, for the first time, PK 11195 was demonstrated to differentially affect glioma cell survival in relation to TSPO expression levels. These results encourage the development of specific-cell strategies for the treatment of gliomas, in which TSPO is highly expressed respect to normal cells.
Chelli
Beatrice
B
Department of Psychiatry, Pharmacology, Neurobiology and Biotechnology, University of Pisa, Pisa, Italy.
Salvetti
Alessandra
A
Da Pozzo
Eleonora
E
Rechichi
Mariarosa
M
Spinetti
Francesca
F
Rossi
Leonardo
L
Costa
Barbara
B
Lena
Annalisa
A
Rainaldi
Giuseppe
G
Scatena
Fabrizio
F
Vanacore
Renato
R
Gremigni
Vittorio
V
Martini
Claudia
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D046529:Microscopy, Electron, Transmission; D051336:Mitochondrial Membranes / Q000378:metabolism; D034622:RNA Interference; D018079:Receptors, GABA / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D000970:Antineoplastic Agents; D007546:Isoquinolines; D018079:Receptors, GABA; C499229:TSPO protein, human; C037850:PK 11195