Inhibition of STAT-3 results in radiosensitization of human squamous cell carcinoma☆
Received 20 April 2009; received in revised form 15 June 2009; accepted 24 June 2009. published online 21 July 2009.
Abstract
Background
Signal transducer and activator of transcription-3 (STAT-3) is a downstream component of the Epidermal Growth Factor Receptor (EGFr) signaling process that may facilitate the resistance of tumor cells to conventional cancer treatments. Studies were performed to determine if inhibition of this downstream protein produces radiosensitization.
Methods/Results
A431 cells (human squamous cell carcinoma cells with EGFr overexpression) were found to be sensitized to radiation after treatment with STAT-3 small interfering RNA (siRNA). Therefore, a short hairpin RNA (shRNA) against STAT-3 was designed and cloned into a pBABE vector system modified for shRNA expression. Following transfection, clone 2.1 was selected for further study as it showed a dramatic reduction of STAT-3 protein (and mRNA) when compared to A431 parental cells or a negative control shRNA cell line (transfected with STAT-3 shRNA with 2 base pairs mutated). A431 2.1 showed doubling times of 25–31h as compared to 18–24h for the parental cell line. The A431 shRNA knockdown STAT-3 cells A431 were more sensitive to radiation than A431 parental or negative STAT-3 control cells.
Conclusion
A431 cells stably transfected with shRNA against STAT-3 resulted in enhanced radiosensitivity. Further work will be necessary to determine whether the inhibition of STAT-3 phosphorylation is a necessary step for the radiosensitization that is induced by the inhibition of EGFr.
The University of Alabama at Birmingham, Department of Radiation Oncology, AL, USA
Corresponding author. Address: Department of Radiation Oncology, The University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35233, USA.
☆ Presented at the 11th International Wolfsberg Meeting, 2009.
ABSTRACT