Abstract 3446: Stat3 is a potential molecular target for chemoradiosensitization of colorectal cancer cells

Abstract

Introductory sentence: Resistance to preoperative chemoradiotherapy represents a major clinical problem in the treatment of patients with locally advanced rectal cancer. Therefore, the identification of novel molecular targets that are differently expressed in responsive and resistant tumors is exceedingly important. Furthermore, modulating target gene expression may sensitize a priori resistant tumors to multimodal therapy. Experimental procedures: Previously, we established an in vitro model for chemoradiotherapy in 12 colorectal cancer cell lines, and correlated differences in treatment sensitivity with pretherapeutic gene expression profiles. Within our signature we identified the signal transducer and activator of transcription 3 (STAT3), which was significantly correlated with treatment resistance. To test the functional relevance of the observed over-expression of STAT3, we first determined STAT3 mRNA and protein expression levels in all 12 cell lines. Subsequently, we established doxycycline-inducible stable shRNA single cell populations and a non-silencing shRNA (shNEG) in SW480. The induced single cell clones and shNEG were treated with 3µM 5-FU and exposed to 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). Successful RNAi-mediated silencing of STAT3 and inhibitor treatment was detected by Western blot. Data: STAT3 was significantly overexpressed in resistant cells at mRNA and protein level. In stable STAT3 knockdown single cell clones and transiently siRNA transfected SW480 and SW837 cells, successful silencing of the STAT3 protein was detected after 72 hours, and STATTIC-induced inhibition of STAT3-phosphorylation after 1 hour. The silencing/inhibition resulted in a significantly increased chemoradiosensitivity with dose-reduction factors of 1.8 to 2. Conclusions: STAT3 is highly overexpressed in resistant colorectal cancer cells, and silencing of STAT3 leads to a significantly increased chemoradiosensitivity. This highlights the potential relevance of STAT3 as a novel molecular target in rectal cancer to sensitize a priori resistant colorectal tumor cells to chemoradiotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3446. doi:1538-7445.AM2012-3446