Akt signaling pathway: a target for radiosensitizing human malignant glioma.
Radiation therapy plays a central role in the treatment of glioblastoma, but it is not curative due to the high tumor radioresistance. Phosphatidyl-inositol 3-kinase/protein kinase B (Akt) and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways serve to block the apoptosis process, keeping cells alive in very toxic environments such as chemotherapy or ionizing radiation. In the present study, from a panel of 8 human malignant glioma cell lines, investigations on the relationship between intrinsic radioresistance and Akt or STAT3 basal activation were done. Secondly, the impact of down-modulation of Akt or STAT3 signaling on in vitro intrinsic radiosensitivity was evaluated. Using a clonogenic cell survival assay, our results revealed a significant correlation between the basal Akt activation and the surviving fraction at 2 Gy (SF2). In contrast, no correlation was found between STAT3 activation and SF2. According to this, down-modulation of Akt with a specific chemical inhibitor (Akt inhibitor IV) demonstrated a significant enhancement of radiation sensitivity on glioma cells in a clonogenic survival assay. On the contrary, down-modulation of STAT3 signaling with a specific chemical inhibitor (JSI-124) or a neutralizing gp130 antibody failed to radiosensitize glioma cells. These data indicate that the Akt intercept node could be a more relevant therapeutic target than STAT3 for radiosensitizing human malignant glioma.
Chautard
Emmanuel
E
Centre Jean Perrin, Laboratoire de Radio-Oncologie Expérimentale, EA 3846 Thérapie Ciblée Combinatoire en Onco-Hématologie, Université d'Auvergne, Clermont-Ferrand, France. emmanuel.chautard@cjp.fr
Loubeau
Gaëlle
G
Tchirkov
Andreï
A
Chassagne
Jacques
J
Vermot-Desroches
Claudine
C
Morel
Laurent
L
Verrelle
Pierre
P
D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011836:Radiation Tolerance / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051057:Proto-Oncogene Proteins c-akt
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