Int6/eIF3e is essential for proliferation and survival of human glioblastoma cells.
Glioblastomas (GBM) are very aggressive and malignant brain tumors, with frequent relapses despite an appropriate treatment combining surgery, chemotherapy and radiotherapy. In GBM, hypoxia is a characteristic feature and activation of Hypoxia Inducible Factors (HIF-1α and HIF-2α) has been associated with resistance to anti-cancer therapeutics. Int6, also named eIF3e, is the "e" subunit of the translation initiation factor eIF3, and was identified as novel regulator of HIF-2α. Eukaryotic initiation factors (eIFs) are key factors regulating total protein synthesis, which controls cell growth, size and proliferation. The functional significance of Int6 and the effect of Int6/EIF3E gene silencing on human brain GBM has not yet been described and its role on the HIFs is unknown in glioma cells. In the present study, we show that Int6/eIF3e suppression affects cell proliferation, cell cycle and apoptosis of various GBM cells. We highlight that Int6 inhibition induces a diminution of proliferation through cell cycle arrest and increased apoptosis. Surprisingly, these phenotypes are independent of global cell translation inhibition and are accompanied by decreased HIF expression when Int6 is silenced. In conclusion, we demonstrate here that Int6/eIF3e is essential for proliferation and survival of GBM cells, presumably through modulation of the HIFs.
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. julie.sesen@hotmail.fr.
Julie
J
Sesen
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. anne.cammas@inserm.fr.
Anne
A
Cammas
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. sarah.scotland1@gmail.com.
Sarah J
SJ
Scotland
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. elefterion.bertrand@live.fr.
Bertand
B
Elefterion
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. lemarie.anthony@claudiusregaud.fr.
Anthony
A
Lemarié
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. stefania.millevoi@inserm.fr.
Stefania
S
Millevoi
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. mathewl@mail.med.upenn.edu.
Lijoy K
LK
Mathew
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. cathy.seva@inserm.fr.
Cathy
C
Seva
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. toulas.christine@claudiusregaud.fr.
Christine
C
Toulas
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. moyal.elizabeth@claudiusregaud.fr.
Elizabeth Cohen-Jonathan
EC
Moyal
INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, 20-24 Rue du Pont St Pierre, 31052 Toulouse, Cedex, France. nicolas.skuli@inserm.fr.
Nicolas
N
Skuli
D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D034622:RNA Interference
D039621:Eukaryotic Initiation Factor-3; D051795:Hypoxia-Inducible Factor 1, alpha Subunit