Overexpression of EGFR is one of the most prominent abnormalities associated with GBMs. Approximately 50% of GBMs selleckchem Ruxolitinib contain over active EGFR, typically through EGFR gene amplification or the expression of an active EGFR mutant. The expression of EGFRvIII, a common constitutively active EGFR mutant, increases radioresist ance in immortalized normal human astrocytes. Clinical studies have also shown that EGFR promotes resistance to radiation in many tumor types, including GBMs. Although we did not demonstrate the direct activation of EGFR by IR in this study, this observation has been reported by others. For example, Bowers et al reported that radiation induces EGFR tyrosine phosphor ylation in MDA MB 231 human breast cancer cells min utes after irradiation.

Considering that the EGFR inhibitor AG1478 significantly reduced IR induced Akt activation, it is conceivable that IR induces PI3K Akt acti vation through EGFR Inhibitors,Modulators,Libraries activation. Increased Akt activation is associated with radiation resist ance in various tumor types. However, most experiments have compared the radiosensitivity of cells with different levels of basal Akt activation. Since active Akt promotes cell proliferation and inhibits apoptosis, cells with elevated basal Akt activation usually have much higher clone formation efficiency. For example, Inhibitors,Modulators,Libraries we found that in medium containing doxycycline, the plating effi ciency was much lower in U87MG cells expressing wild type PTEN as opposed to mutant PTEN genes. To account for this difference, our study focused on the effect of IR induced Akt activation instead of basal Akt activation.

Therefore, Akt activation was only inhib ited by treatment with a drug, or with an inducible mutant, for a short period of time before and after irradi ation, such that Akt activation was not altered during clone formation and clone formation efficiency remained constant. Using U87MG cells we showed that inhibiting IR induced Akt activation increases radiosensitivity. It is possible Inhibitors,Modulators,Libraries that Akt participates in a feedback loop whereby activation of Akt induced by IR increases the radioresist ance of Inhibitors,Modulators,Libraries GBM cells. Among the eight GBM cell lines tested for Akt activation, both LN18 and LN229 contain wild type PTEN, and irra diation Inhibitors,Modulators,Libraries induced Akt activation in LN18 cells, but not in LN229 cells. All of the other six GBM cell lines contain mutant PTEN, but the effects of radiation on Akt activa tion were not consistent. Further experiments are needed to determine if activation of Akt by irradiation is related to the genetic status of PTEN or other factors critical to this Wortmannin 19545-26-7 signaling pathway. Conclusion In conclusion, our findings indicate that Akt activation may have a critical role in radiosensitivity in a subset of GBM cells.