STAT3 as a potential molecular target to sensitize colorectal cancer cells to chemoradiotherapy.

Abstract

434 Background: Resistance to preoperative chemoradiotherapy represents a major clinical problem in the treatment of patients with locally advanced rectal cancer. Therefore, the identification of molecular biomarkers that differentiate responsive and resistant tumors is exceedingly important, because this may lead to the identification of novel molecular targets whose modification could be harnessed to sensitize a priori resistant tumors to multimodal treatment. Methods: We recently established an in vitro model for 5-FU based chemoradiotherapy, and correlated differences in treatment sensitivity of 12 colorectal cancer cell lines with pretherapeutic gene expression profiles. One gene the expression of which correlated positively with treatment resistance was the signal transducer and activator of transcription 3, STAT3. To test the functional relevance of this observation, we first determined STAT3 mRNA and protein expression levels in all cell lines. Next, we established doxycycline-inducible stable shRNA single-cell clone (SCC) populations. Successful silencing of STAT3 was detected by Western blot analysis. The induced SCCs were treated with 3 µM 5-FU, and subsequently exposed to 0, 1, 2, 4, 6, and 8 Gy of X-rays. In addition, STAT3 was inhibited using two different siRNAs, and a small-molecular inhibitor (STATTIC). Results: STAT3 was significantly overexpressed in resistant cells. In SW480 and SW837 cells, both shRNA- and siRNA-mediated silencing as well as STATTIC-induced inhibition of STAT3-phosphorylation resulted in a significantly increased chemoradiosensitivity, with dose-reduction factors of 1.8 to 2. Conclusions: These results highlight the potential relevance of STAT3 as a novel molecular target to sensitize a priori resistant tumor cells to chemoradiotherapy.