ErbB-2 signaling is involved in regulating PSA secretion in androgen-independent human prostate cancer LNCaP C-81 cells

Ming Shyue Lee, Tsukasa Igawa, Ta Chun Yuan, Xiu Qing Zhang, Fen Fen Lin, Ming Fong Lin

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

The expression and secretion of prostate-specific antigen (PSA) are regulated by androgens in normal prostate secretory epithelial cells. In prostate cancer patients, the serum PSA level is usually elevated and cancer cells are initially responsive to androgens. However, those cancer cells become androgen-independent after androgen ablation therapy. In hormone-refractory cancer patients, even in an androgen-deprived environment, the circulation level of PSA rebounds and is constitutively elevated through a yet unknown mechanism. Tyrosine phosphorylation of ErhB-2 is involved in regulating the androgen-responsive phenotype of prostate cancer cells, and it is at least partly regulated by the cellular form of prostatic acid phosphatase (PAcP), a prostate-unique protein tyrosine phosphatase. We investigated the ErhB-2 signal pathway in androgen-independent PSA secretion. LNCaP C-81 cells, which are androgen-independent LNCaP cells lacking endogenous PAcP expression with a hypertyrosine phosphorylated ErhB-2, secreted a higher level of PSA in conditioned media than did androgen-sensitive LNCaP C-33 parental cells. A restored expression of cellular PAcP in C-81 cells was concurrent with a decrease in tyrophosphorylation of ErhB-2 and reduction of PSA secretion. Moreover, transient transfection of C-33 cells with the wild-type ErhB-2 or a constitutively active mutant of MEK1 cDNA resulted in an increased level of secreted PSA. The elevation of secreted PSA level by the forced expression of ErhB-2 was inhibited by an MEK inhibitor, PD98059. In C-81 cells, the expression of a dominant negative mutant of ErhB-2 reduced the secreted level of PSA. The inhibition of ErhB-2 or mitogenactivated protein (MAP) kinases by specific inhibitors AG879, AG825, or PD98059 led to a decrease in PSA secretion. Taken together, our data clearly indicate that the ErbB-2 signal pathway via MAP kinases (ERK1/2) is involved in regulating the secretion of PSA by androgen-independent human prostate cancer LNCaP C-81 cells in an androgen-depleted environment.

Original languageEnglish (US)
Pages (from-to)781-796
Number of pages16
JournalOncogene
Volume22
Issue number5
DOIs
StatePublished - Feb 6 2003

Keywords

  • Androgen independence
  • ErbB-2
  • MAP kinases
  • PSA secretion
  • Prostate cancer
  • Prostatic acid phosphatase
  • Protein tyrosine kinase
  • Protein tyrosine phosphatase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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