Abstract
Abstract Colorectal carcinoma (CRC) patients show resistance to EGFR-TKI (epidermal growth factor receptor -tyrosine kinase inhibitor) treatment. Protease-activated receptor 2 (PAR2) has been shown to transactivate EGFR. We aim to investigate whether PAR2 sensitizes EGFR-TKI-induced apoptosis in CRC. Firstly, inhibition of PAR2 with shRNA or ENMD-1068 (a selective antagonist of PAR2) significantly sensitized EGFR-TKI (gefitinib or AG1478)-induced apoptosis, which was measured with Annexin V/ PI staining and activation of caspase-3 in different CRC cell lines. In xenograft tumor model, gefitinib treatment dramatically reduced the tumor volume in HT-29-shPAR2 compared with HT-29-vector. Mechanism study showed that PAR2 knockdown significantly reduced bcl-xL expression at both mRNA and protein level. Consistently, activation of PAR2 upregulated bcl-xL. Furthermore, inhibition of protein phosphatase (PP) with okadaic acid significantly downregulated bcl-xL. Moreover, knockdown of PP1 with siRNA blocked PAR2-induced accumulation of bcl-xL. In summary, our findings suggest that inhibition of PAR2 sensitizes EGFR-TKI-induced apoptosis via downregulation of bcl-xL in colorectal cancer. Considering the extensive expression of PAR2 and PAR2-activating proteases in colon, it strongly indicates that inhibition of PAR2 may be a potential avenue to overcome EGFR-TKI resistance in patients with CRC. Citation Format: Weiwei Li, Yiming Ma, Longmei He, Hongying Wang. Deficiency of protease-activated receptor 2 signaling sensitizes EGFR-TKI-induced apoptosis in colorectal cancer [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 2319. doi:10.1158/1538-7445.AM2017-2319
Published Version
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