mTOR signaling pathway is a target for the treatment of colorectal cancer

Abstract

Background: mTOR signaling has been suggested to be an important factor involved in tumorigenesis, but its role in human colorectal cancer (CRC) has not been completely elucidated. Herein, the purpose of this study was to analyze the distribution pattern of mTOR signaling components in CRC and adenoma and to determine whether targeted inhibition of mTOR could be a potential therapeutic strategy for CRC.

Methods: Immunohistochemical analysis was performed on human CRC and adenoma for mTOR signaling components, including mTOR, p70s6 K, and 4EBP1. HCT116 and SW480 human CRC cell lines were treated with siRNA directed against mTOR, and cell viability, cell cycle, and apoptosis were assessed. HCT116 and SW480 cells were injected into athymic nude mice to establish a CRC xenograft model. Mice were randomly transfected with either nontargeting control or mTOR siRNA, and tumor volume, mTOR signaling activity, and apoptosis were evaluated.

Results: mTOR signaling components, including mTOR, p70s6 K, and 4EBP1, were highly activated in glandular elements of CRC and colorectal adenomas with high-grade intraepithelial neoplasia (HIN), with a correlation between staining intensity and depth of infiltration in CRC. Inhibition of mTOR expression using a specific mTOR siRNA resulted in considerably decreased in vitro and in vivo cell growth.

Conclusions: mTOR signaling is associated with the clinical pathological parameters of human CRC. siRNA-mediated gene silencing of mTOR may be a novel therapeutic strategy for CRC.