Abstract
Glioblastoma (GBM) is one of most malignancy tumors worldwide. Temozolomide (TMZ) is an important chemotherapy drug in GBM therapy. However, acquired TMZ-resistance frequently happens in GBM therapy and leads to high percentage of GBM recurrence. In our study, we demonstrated that Snail is upregulated in recurrent GBM tumors, and promotes the GBM cells resistant to TMZ induced apoptosis. Enhanced expression of Snail compromises the apoptosis induced by TMZ, and increases the cell migration and invasion. Reversely, depletion of Snail by siRNA has the opposite effects. In addition, we confirmed that the expression of Snail is modulated by STAT3 activation, since phospho-STAT3 level is relatively higher in recurrent GBM tumors and TMZ resistant cells. Knockdown of STAT3 turns down the expression of Snail in protein and mRNA level, and thereby sensitized the resistant GBM cells to TMZ treatment. Interestingly, the activation of STAT3 in GBM resistant cells is modulated by IL-6 secretion. Suppression of IL-6 abandons the STAT3 activation, and reduces its binding with Snail promoter. Inhibition of IL-6 by its antibody enhanced the killing effects of TMZ both in vivo and in vitro. Overall, our results provided a rational to overcome the TMZ resistant in GBM treatment by targeting IL-6-STAT3-Snail pathway.