Abstract
Abstract The resistance of gefitinib has been revealed to complicate cancer therapy. Tetraiodothyroacetic acid (tetrac) and its nanoparticulate derivative (NDAT, nano-tetrac) have been proved in vitro and in vivo xenograft demonstrating anti-proliferative and anti-angiogenetic activities. It also indicates that they potentiate anti-cancer agent-induced anti-proliferation in cancer cells. In this study, we investigated the effects of NDAT on gefitinib-induced anti-cancer activities in human colorectal cancer cells. Gefitinib inhibited cell proliferation at concentration 1 μM in K-ras wild type HT29 cell and NDAT enhanced the anti-proliferation-induced gefitinib significantly. Meanwhile, both inhibited proliferative and metastatic genes expression in HT29 cells. On the other hand, 10 μM gefitinib inhibited cell proliferation in K-ras mutant HCT116 cell which was further enhanced by NDAT. Different from results in HT-29 cells, only NDAT inhibited proliferative and metastatic genes expression significantly and enhanced the effect of gefitinib in HCT116 cells. ST6Gal-1 catalyzes sialylation of EGFR and induces gefitinib-resistant in colorectal cancers. In addition, NDAT did reduced not only ST6Gal-1 gene expression, but also its protein production. However, the inhibition of ST6Gal-1 expression may not be sufficient to induced anti-proliferation in colorectal cancer cells. PI3K inhibitor, LY294002, was able to potentiate the gefitinib-induced anti-proliferation in HCT116 cells suggesting that constitutive activation of PI3K may play a key role on gefitinib-resistance in HCT116 cells. In summary, NDAT potentiated gefitinib-induced anti-proliferation via inhibiting the activity of ST6Gal-1 and PI3K activation in gefitinib-resistant colorectal cancer cells. Citation Format: Yu-Tang Chin, Chi-Yu Lin, Chun A. Changou, Jacqueline Whang-Peng, Paul J. Davis, Hung-Yun Lin. Nano-tetraiodothyroacetic acid (NDAT) potentiates gefitinib-induced antiproliferation in colorectal cancer cells by inhibiting EGFR sialylation and PI3K activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2042. doi:10.1158/1538-7445.AM2017-2042
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