STAT3 Serine 727 Phosphorylation: A Relevant Target to Radiosensitize Human Glioblastoma.
Radiotherapy is an essential component of glioma standard treatment. Glioblastomas (GBM), however, display an important radioresistance leading to tumor recurrence. To improve patient prognosis, there is a need to radiosensitize GBM cells and to circumvent the mechanisms of resistance caused by interactions between tumor cells and their microenvironment. STAT3 has been identified as a therapeutic target in glioma because of its involvement in mechanisms sustaining tumor escape to both standard treatment and immune control. Here, we studied the role of STAT3 activation on tyrosine 705 (Y705) and serine 727 (S727) in glioma radioresistance. This study explored STAT3 phosphorylation on Y705 (pSTAT3-Y705) and S727 (pSTAT3-S727) in glioma cell lines and in clinical samples. Radiosensitizing effect of STAT3 activation down-modulation by Gö6976 was explored. In a panel of 15 human glioma cell lines, we found that the level of pSTAT3-S727 was correlated to intrinsic radioresistance. Moreover, treating GBM cells with Gö6976 resulted in a highly significant radiosensitization associated to a concomitant pSTAT3-S727 down-modulation only in GBM cell lines that exhibited no or weak pSTAT3-Y705. We report the constitutive activation of STAT3-S727 in all GBM clinical samples. Targeting pSTAT3-S727 mainly in pSTAT3-Y705-negative GBM could be a relevant approach to improve radiation therapy.
Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.|Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France.|Laboratoire de Pharmacologie, de Toxicologie et de Chimie Thérapeutique, Université de Ouagadougou, 03 BP 7021, OUAGADOUGOU 03, BURKINA FASO.
Zangbéwendé Guy
ZG
Ouédraogo
Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.|Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France.
Mélanie
M
Müller-Barthélémy
Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.|CHU Clermont-Ferrand, Service d'Anatomopathologie, F-63003, CLERMONT-FERRAND, France.
Jean-Louis
JL
Kemeny
Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.|Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France.
Véronique
V
Dedieu
Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.|Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France.|Institut Curie, CNRS UMR3347, INSERM U2021, 91405, Orsay, France.
Julian
J
Biau
CHU Clermont-Ferrand, Service de Neurochirurgie, F-63003, CLERMONT-FERRAND, France.|Clermont Université, Université d'Auvergne, EA 7282, IGCNC, BP 10448, F-63000, CLERMONT-FERRAND, France.
Toufic
T
Khalil
Centre Jean Perrin, Service D'anatomopathologie, F-63000, CLERMONT-FERRAND, France.
Lala Ines
LI
Raoelfils
INSERM, UMR1052, Radiobiology Group, Lyon, France.
Adeline
A
Granzotto
CHU Clermont-Ferrand, Biostatistics unit, DRCI, F-63003, CLERMONT-FERRAND, France.
Bruno
B
Pereira
Clermont Université, Université Blaise-Pascal, GReD, UMR CNRS 6293, INSERM U1103, 24 Avenue des Landais BP80026, 63171 Aubière 63177, AUBIERE, France.
Claude
C
Beaudoin
Laboratoire de Pharmacologie, de Toxicologie et de Chimie Thérapeutique, Université de Ouagadougou, 03 BP 7021, OUAGADOUGOU 03, BURKINA FASO.
Innocent Pierre
IP
Guissou
Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.|CHU Clermont-Ferrand, Service d'Hématologie Biologique/Immunologie, F-63003, CLERMONT-FERRAND, France.
Marc
M
Berger
Clermont Université, Université Blaise-Pascal, GReD, UMR CNRS 6293, INSERM U1103, 24 Avenue des Landais BP80026, 63171 Aubière 63177, AUBIERE, France.
Laurent
L
Morel
Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.|Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France.
Emmanuel
E
Chautard
Clermont Université, Université d'Auvergne, EA 7283, CREaT, BP 10448, F-63000, CLERMONT-FERRAND, France.|Centre Jean Perrin, Service Radiothérapie, Laboratoire de Radio-Oncologie Expérimentale, F-63000, CLERMONT-FERRAND, France.
Pierre
P
Verrelle
D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy*; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011827:Radiation; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013053:Spectrophotometry; D018709:Statistics, Nonparametric; D013997:Time Factors; D014965:X-Rays
D002227:Carbazoles; D004791:Enzyme Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C081021:Go 6976; D012694:Serine
Gö6976; STAT3; glioma; radiotherapy; resistance