Co-overexpression of Bag-1 and heat shock protein 70 in human epidermal squamous cell carcinoma: Bag-1-mediated resistance to 5-fluorouracil-induced apoptosis

Br J Cancer. 2011 Apr 26;104(9):1459-71. doi: 10.1038/bjc.2011.111.

Abstract

Background: The aim was to determine whether Bcl-2-associated athanogene-1 (Bag-1) and/or its binding protein heat shock protein-70 (Hsp70) exhibit deregulated expression in epidermal squamous cell carcinoma (SCC) and whether Bag-1 confers apoptosis resistance.

Method: Immunohistochemistry for Bag-1 and Hsp70 was performed on 60 epidermal SCC and 10 normal skin samples. The epidermal SCC cell line SCC-13 was treated with 5-fluorouracil (5-FU) after Bag-1 knockdown to determine whether high Bag-1 levels contribute to growth and/or apoptosis resistance.

Results: Normal epithelium expressed primarily nuclear Bag-1. Most tumours showed reduced nuclear Bag-1 staining, but a subset exhibited strong Bag-1 staining, with cytoplasmic Bag-1 staining intensity correlating with cytoplasmic Hsp70 staining intensity (r(s)=0.462; P<0.001) and less differentiation (P<0.001). Bag-1 knockdown resulted in markedly reduced SCC-13 cell yield, increased spontaneous apoptosis and enhanced sensitivity to 5-FU-induced apoptosis. Apoptosis induced by 5-FU in the Bag-1-knockdown cells was significantly greater than the additive apoptotic effect of 5-FU or Bag-1 knockdown alone.

Conclusions: Overexpression of Bag-1 and Hsp70 in poorly differentiated SCC may confer both enhanced tumour cell growth and apoptosis resistance. Bag-1 may contribute to the resistance of more advanced epidermal SCC to chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drug Resistance, Neoplasm* / drug effects
  • Fluorouracil / pharmacology*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HSP70 Heat-Shock Proteins / metabolism*
  • Humans
  • Immunohistochemistry
  • Keratinocytes / metabolism
  • RNA, Small Interfering
  • Skin / metabolism
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Up-Regulation

Substances

  • Antimetabolites, Antineoplastic
  • BCL2-associated athanogene 1 protein
  • DNA-Binding Proteins
  • HSP70 Heat-Shock Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • Fluorouracil