Abstract 2338: EGFR-mediated TGM2 overexpression couples acquired TRAIL-resistance and migration involving c-FLIP and MMP9 in NSCLC cells

Abstract

Abstract Acquired chemoresistance not only blunts cancer chemotherapy, but may also promote cancer cell migration and metastasis. Our previous studies have revealed that acquired tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in non-small cell lung cancer (NSCLC) cells was associated with Akt-mediated stabilization of cellular FLICE-like inhibitory protein (c-FLIP) and myeloid cell leukemia 1 (Mcl-1). The cells with acquired TRAIL-resistance have significantly increased migration and invasion potential. Gene expression array assay was used to explore the mechanism underlying TRAIL-resistance associated migration, and tissue transglutaminase 2 (TGM2) was identified as one of the genes with the highest expressing increase in TRAIL-resistant cells. Suppressing TGM2 activity or expression dramatically alleviated TRAIL-resistance and cell migration, suggesting TGM2 contributes to the both phenotypes in the TRAIL-resistant cells. TGM2 suppression significantly reduced c-FLIPL but not Mcl-1L expression, suggesting that TGM2 mediates TRAIL-resistance through c-FLIP. The expression of MMP9, a matrix metalloproteinase involved in cancer cell migration, was suppressed when TGM2 was inhibited, suggesting that TGM2 potentiates cell migration through upregulating MMP-9 expression. Furthermore, we found that EGFR was highly upregulated and activated and suppression of which dramatically reduced the expression level of TGM2 in the TRAIL-resistant cells. With chemical inhibitors, we further determined MAPKs (JNK and ERK), but not Akt and NF-κB, are responsible for EGFR-mediated TGM2 expression. Conversely, suppression of TGM2 had no effect on ERK, JNK and Akt activity. These results identify a novel pathway that involves EGFR, MAPK and TGM2 for acquired TRAIL-resistance and cell migration in NSCLC cells. Because TGM2 converges acquired TRAIL-resistance and cell migration, it could be a molecular target for circumventing acquired chemoresistance and metastasis in lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2338. doi:10.1158/1538-7445.AM2011-2338