Oral squamous cell carcinoma (OSCC) is one of the most common neoplasms worldwide. Previously, we identified the angiostatic agent tryptophanyl-tRNA synthetase (TrpRS) as a dysregulated protein in OSCC based on a proteomics approach. Herein, we show that TrpRS is overexpressed in OSCC tissues (139/146, 95.2%) compared with adjacent normal tissues and that TrpRS expression positively correlates with tumor stage, overall TNM stage, perineural invasion and tumor depth. Importantly, the TrpRS levels were significantly higher in tumor cells from metastatic lymph nodes than in corresponding primary tumor cells. TrpRS knockdown or treatment with conditioned media obtained from TrpRS-knockdown cells significantly reduced oral cancer cell viability and invasiveness. TrpRS overexpression promoted cell migration and invasion. In addition, the extracellular addition of TrpRS rescued the invasion ability of TrpRS-knockdown cells. Subcellular fractionation and immunofluorescence staining further revealed that TrpRS was distributed on the cell surface, suggesting that secreted TrpRS promotes OSCC progression via an extrinsic pathway. Collectively, our results demonstrated the clinical significance and a novel role of TrpRS in OSCC.
Karyopherin subunit alpha-2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis in patient. Nevertheless, the regulation of KPNA2 expression in cancers remains unclear. We herein applied epidermal growth factor (EGF) and five EGF receptor (EGFR)-related kinase inhibitors to investigate the role of EGFR signaling in KPNA2 expression in non-small cell lung cancer (NSCLC) cells. We found that EGFR signaling, particularly the mammalian target of rapamycin (mTOR) activity was positively correlated with KPNA2 protein levels in NSCLC cells. The mTOR inhibitors and mTOR knockdown reduced the protein and mRNA levels of KPNA2 in NSCLC and breast cancer cells. Specifically, rapamycin treatment induced proteasome-mediated KPNA2 protein decay and attenuated the transcriptional activation of KPNA2 by decreasing Dp1/E2F1 level in vivo. Immunoprecipitation assay further revealed that KPNA2 physically associated with the phospho-mTOR/mTOR and this association was abolished by rapamycin treatment. Collectively, our results show for the first time that KPNA2 is transcriptionally and post-translationally regulated by the mTOR pathway and provide new insights into targeted therapy for NSCLC.
Prostate cancer is the leading cause of cancer-related death in men in the world. Previous studies have demonstrated that Disabled-2 (DAB2) is a tumor suppressor and down-regulation of DAB2 expression is accompanied with prostate cancer progression. On the other hands, protein kinase C epsilon (PKCε) functions as an oncogene and promotes human prostate cancer cell survival upon treatment of methyseleninic acid (MSA), an anti-cancer agent that induces prostate cancer cell apoptosis. However, little is known whether there is a crosstalk between DAB2 and PKCε. In this study, we first analyzed DAB2 and PKCε protein expression in three prostate cancer cell lines DU145, PC3 and C4-2. Western blot analysis revealed that DAB2 was relatively abundant in PC3 when compared with the DU145 and C4-2 cells. In contrast, the expression of PKCε was higher in DU145 and C4-2 cells when compared with the PC3 cells. Consistent with these findings, ectopic expression of DAB2 resulted in down-regulation of PKCε. These observations implicate a reverse association of DAB2 and PKCε and suggest that DAB2 is a regulator of PKCε expression. To further explore the interplay between DAB2 and PKCε, we determined the effect of DAB2 overexpression on DU145 cell susceptibility to MSA-induced cell death. Consistent with a previous report, overexpression of PKCε increased DU145 cell survival and knockdown of PKCε by small interfering RNA augmented cell death upon treatment of MSA but not Ibupofen. Accordingly, expression of DAB2 down-regulated PKCε and increased in cell susceptibility to MSA that resulted in a 40% decrease of cell survival. These findings suggest that DAB2 modulates PKCε expression and affects prostate cancer cell susceptibility to selective anti-cancer agents. This study represents the first report to unveil the interplay between DAB2, PKCε and prostate cancer cell survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5054.
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