Abstract
Abstract A nonsteroidal anti-inflammatory drug tolfenamic acid (TA) has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which TA exerts its anti-tumorigenic activity is not well understood. Here, we have shown that TA markedly reduced the number of polyps and tumor load in APCmin/+ mice, accompanied with the significant decrease in cyclin D1 expression. Furthermore, we have demonstrated that TA down-regulates cyclin D1 expression in different cancer cells in vitro, coupled by decreasing phosphorylated retinoblastoma protein and increasing cell cycle arrest. Subsequent observation suggests that TA promotes endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) signaling pathway including phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which mediates the repression of cyclin D1 translation. Silence of pancreatic ER eIF2α kinase (PERK) restores cyclin D1 expression in the presence of TA. In conclusion, TA inhibits colorectal cancer cell growth in vitro and blocks colorectal tumorigenesis in a mouse model, at least in part, mediated by inhibiting cyclin D1 translation via ER stress. Support: The University of Tennessee Center of Excellence in Livestock Diseases and Human Health grant (SJB), NIH grant RO1CA108975 (SJB), American Cancer Society grant (RSG-11-133-01-CCE) (S-H Lee), and a grant from the Ministry of Agriculture of the People's Republic of China (2011ZX08008-003) (QL). Citation Format: Xiaobo Zhang, Seong-Ho Lee, Qingwang Li, Seung J. Baek. Tolfenamic acid suppresses intestinal tumorigenesis through inhibiting cyclin D1 translation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-181. doi:10.1158/1538-7445.AM2013-LB-181
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