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- W2316561583 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" @default.
- W2316561583 created "2016-06-24" @default.
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- W2316561583 date "2011-04-15" @default.
- W2316561583 modified "2023-09-27" @default.
- W2316561583 title "Abstract 2338: EGFR-mediated TGM2 overexpression couples acquired TRAIL-resistance and migration involving c-FLIP and MMP9 in NSCLC cells" @default.
- W2316561583 doi "https://doi.org/10.1158/1538-7445.am2011-2338" @default.
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