Journal
CLINICAL CANCER RESEARCH
Volume 17, Issue 13, Pages 4285-4295Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-3236
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Funding
- National Natural Science Foundation [30971482, 81021061]
- Special Public Health Fund [200902002-4]
- National Hightech R&D Program of China [2009AA022706]
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Purpose: To investigate the molecular mechanisms through which polo-like kinase-1 (PLK1) takes part in anoikis resistance of esophageal squamous cell carcinoma (ESCC) cells. Experimental Design: The role of PLK1 in cell anoikis resistance was examined by ectopic gene expression and siRNA-mediated knockdown. Glutathione S-transferase pull-down and co-immunoprecipitation assays were utilized to investigate PLK1-interacting proteins. Electrophoretic mobility shift assay, chromatin immunoprecipitation, and reporter gene assays were carried out to identify the transcription factors responsible for PLK1 expression during anoikis resistance. Results: We found that detachment of ESCC cells triggers the upregulation of PLK1. Elevated PLK1 expression contributes to protection against anoikis in cancer cells through the regulation of beta-catenin expression. Moreover, we showed that, through direct binding to the PLK1 promoter, the NF-kappa B subunit RelA transcriptionally activates PLK1, which inhibits the ubiquitination and degradation of beta-catenin. Inhibition of the NF-kappa B pathway restores the sensitivity of cancer cells to anoikis by downregulating PLK1/beta-catenin expression. In addition, RelA gene amplification and protein overexpression was significantly correlated with PLK1 expression in ESCC tissues. Conclusions: Our findings suggest that upregulation of PLK1 triggered by cell detachment is regulated by RelA at the transcriptional level. PLK1 protects esophageal carcinoma cells from anoikis through modulation of beta-catenin protein levels by inhibiting their degradation. Taken together, this study reveals critical mechanisms involved in the role of RelA/PLK1/beta-catenin in anoikis resistance of ESCC cells. Clin Cancer Res; 17(13); 4285-95. (C) 2011 AACR.
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