Abstract
To investigate the molecular mechanisms through which polo-like kinase-1 (PLK1) takes part in anoikis resistance of esophageal squamous cell carcinoma (ESCC) cells. 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. 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 β-catenin expression. Moreover, we showed that, through direct binding to the PLK1 promoter, the NF-κB subunit RelA transcriptionally activates PLK1, which inhibits the ubiquitination and degradation of β-catenin. Inhibition of the NF-κB pathway restores the sensitivity of cancer cells to anoikis by downregulating PLK1/β-catenin expression. In addition, RelA gene amplification and protein overexpression was significantly correlated with PLK1 expression in ESCC tissues. 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 β-catenin protein levels by inhibiting their degradation. Taken together, this study reveals critical mechanisms involved in the role of RelA/PLK1/β-catenin in anoikis resistance of ESCC cells.
Highlights
Esophageal squamous cell carcinoma (ESCC) is a devastating disease because it metastasizes early and is highly resistant to conventional chemotherapy and radiation therapy
We found that detachment of esophageal squamous cell carcinoma (ESCC) cells triggers the upregulation of polo-like kinase-1 (PLK1)
RelA gene amplification and protein overexpression was significantly correlated with PLK1 expression in ESCC tissues
Summary
Esophageal squamous cell carcinoma (ESCC) is a devastating disease because it metastasizes early and is highly resistant to conventional chemotherapy and radiation therapy. Characterization of the genetic alterations and the downstream effectors that contribute to ESCC metastasis will facilitate the development of effective therapeutic strategies for combating the disease. The extracellular matrix (ECM) provides adhesive support to tissues and controls numerous signals that regulate diverse cellular processes, such as survival, growth, Authors' Affiliations: 1State Key Laboratory of Molecular Oncology and 2Department of Pathology, Cancer Institute (Hospital), Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China. Malignant cells are resistant to anoikis, which leads to enhanced survival after detachment from the supporting matrix and facilitates metastasis [5]. Elucidating the molecular mechanisms involved in cancer-associated anoikis resistance is critical for the development of therapies designed to restore the sensitivity of malignant cells to anoikis
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