Effect of altered WIG-1 expression on DDP sensitivity in a DDP-resistant esophageal squamous cancer cell line

Curr Cancer Drug Targets. 2012 Oct;12(8):950-61. doi: 10.2174/156800912803251252.

Abstract

Esophageal cancer (EC) is the most common esophageal malignancy and has a dismal prognosis. Developing novel strategies to reverse the resistance to chemotherapeutics in EC is currently of intense interest. The wide-type p53 induced gene 1 (WIG-1) is a p53-regulated transcription factor. The effect of WIG-1 on the regulation of cisplatin (DDP) sensitivity was evaluated in DDP-resistant EC cells both in vitro and in vivo. The DDP-resistant sub-line EC109/DDP was successfully selected following eight months of culture. Overexpression of WIG-1 in EC109/DDP cells significantly lowered the IC(50) of DDP to 1.11 ± 0.54 μg/ml when compared to Control cells (4.57 ± 0.98 μg/ml, P < 0.05). In addition, WIG-1 exerted a negative effect on cell proliferation and on the cloning efficiency of EC109/DDP cells. A significant increase in the apoptosis index and in TUNEL-positive nuclei was observed when the expression of WIG-1 was upregulated. Furthermore, WIG-1-overexpressing DDP-resistant EC cells exhibited suppressed xenograft tumor growth and a lower green fluorescent protein (GFP) fluorescence intensity following DDP injection. WIG-1 also reduced the expression of ERCC1 and increased the expression of Bax in DDP-resistant EC cells, while the expression of Bcl-2, P-gp and GST-π was not significantly altered after up- or down-regulation of WIG-1. In summary, these results show that WIG-1 may reverse the DDP resistance of EC cells by reducing ERCC1 expression and increasing Bax expression. This study will provide a framework for understanding the mechanism of DDP resistance by WIG-1 and will aid in the therapeutic use of DDP in ESCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Base Sequence
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Sequence Data
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • RNA-Binding Proteins
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • ZMAT3 protein, human
  • Cisplatin