In some cell lines and higher doses of BEZ235 may overcome the negative feedback of mTORC1/S6 kinase 1 feedback loop. Although p-AKT was activated in 8505C and KAT4C, BEZ235 had better inhibitory effects in these cell lines as compared to TT and BHP7-13, suggesting that other molecules affected by BEZ235 play a more important role in determining therapeutic outcome. We found that the expression of p-S6 ribosomal protein and p27 correlate with the sensitivity of BEZ235 in thyroid cancer. S6 ribosomal protein is a downstream of S6 kinase 1, which is activated by mTORC1. Phosphorylation of S6 ribosomal protein increases translational control of protein synthesis and enhances cell growth. Cells with higher levels of p-S6 ribosomal protein are more susceptible to BEZ235, suggesting that the inhibition of mTORC1 and S6 ribosomal protein is the major therapeutic effect of BEZ235. p-S6 ribosomal protein has also recently been recognized as a marker to predict therapeutic effect of an mTOR inhibitor in sarcoma. In this study, thyroid cancer lines with higher expressions of p-S6 ribosomal protein also showed lower levels of p27. This finding suggests S6 ribosomal protein is a suppressor of p27 in thyroid cancer, and may explain why both p-S6 ribosomal protein and p27 were predictors of sensitivity to BEZ235. Interestingly, p27 was previously noted to have an inverse association with the activity of the PI3K/mTOR pathway in thyroid cancer cells, and repression of this pathway increases p27. 4E-BP1 is another protein downstream of mTORC1. Inhibition of mTORC1 leads to dephosphorylation of 4E-BP1, enhancing the binding of 4E-BP1to eIF4E, and blocking protein translation and cell (S)-Tedizolid proliferation. Although BEZ235 affects both S6 ribosomal protein and 4E-BP1 efficiently, only p-S6 ribosomal protein expression predicts for sensitivity to BEZ235 in this study. In ovarian cancer, biomarkers predicting susceptibility of BEZ235 were reported, and the expression of p-4E-BP1 did correlate with the sensitivity of BEZ235. In addition to inhibiting cell cycle progression, BEZ235 caused apoptosis in two of six cell lines. The inhibition of cell cycle progression is a known effect of BEZ235, even at lower doses. However, apoptosis 1629249-40-6 cost appears in only some cancer cell lines and is more apparen
