Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

Carrión-Salip,Dolors; Panosa,Clara; Menendez,Javier  A.; Puig,Teresa; Oliveras,Glòria; Pandiella,Atanasio; De Llorens,Rafael; Massaguer,Anna

doi:10.3892/ijo.2012.1509

September 2012 Volume 41 Issue 3

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September 2012 Volume 41 Issue 3

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Article

Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

Authors:
- Dolors Carrión-Salip
- Clara Panosa
- Javier A. Menendez
- Teresa Puig
- Glòria Oliveras
- Atanasio Pandiella
- Rafael De Llorens
- Anna Massaguer
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Affiliations: Biochemistry and Molecular Biology Unit, Department of Biology, University of Girona, Girona 17071, Spain, Unit of Translational Research, Catalan Institute of Oncology-Girona, Dr Josep Trueta University Hospital, Girona 17007, Spain, Department of Medical Science, Girona Institute for Biomedical Research, University of Girona, Girona 17071, Catalonia, Spain, Institute of Molecular and Cellular Biology of Cancer, University of Salamanca, Salamanca 37007, Spain
Pages: 1128-1138
|
Published online on: June 6, 2012

https://doi.org/10.3892/ijo.2012.1509
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Abstract

The deregulation of the epidermal growth factor receptor (EGFR) pathway plays a major role in the pathogenesis of prostate cancer (PCa). However, therapies targeting EGFR have demonstrated limited effectiveness in PCa. A potential mechanism to overcome EGFR blockade in cancer cells is the autocrine activation of alternative receptors of the human EGFR (HER) family through the overexpression of the HER receptors and ligands. In the present study, we were interested in analyzing if this intrinsic resistance mechanism might contribute to the inefficacy of EGFR inhibitors in PCa. To this end, we selected two androgen-independent human prostate carcinoma cell lines (DU145 and PC3) and established DU145 erlotinib-resistant cells (DUErR). Cells were treated with three EGFR inhibitors (cetuximab, gefinitib and erlotinib) and the sensitivity to each treatment was assessed. The gene expression of the four EGFR/HER receptors and seven ligands of the HER family was analyzed by real-time PCR prior to and after each treatment. The receptors expression and activation were further characterized by flow cytometry and western blot analysis. EGFR inhibition rapidly induced enhanced gene expression of the EGF, betacellulin and neuregulin-1 ligands along with HER2, HER3 and HER4 receptors in the DU145 cells. In contrast, slight changes were observed in the PC3 cells, which are defective in the phosphatase and tensin homolog (PTEN) tumor suppressor gene. In the erlotinib-resistant DUErR cells, the expression of HER2 and HER3 was increased at mRNA and protein levels together with neuregulin-1, leading to enhanced HER3 phosphorylation and the activation of the downstream PI3K/Akt survival pathway. HER3 blockage by a monoclonal antibody restored the cytostatic activity of erlotinib in DUErR cells. Our results confirm that the overexpression and autocrine activation of HER3 play a key role in mediating the resistance to EGFR inhibitors in androgen-independent PCa cells.

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Medicine International

Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

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