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

Oncogene volume 22, pages 781–796 (2003)Cite this article

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 ErbB-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 ErbB-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 ErbB-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 ErbB-2 and reduction of PSA secretion. Moreover, transient transfection of C-33 cells with the wild-type ErbB-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 ErbB-2 was inhibited by an MEK inhibitor, PD98059. In C-81 cells, the expression of a dominant negative mutant of ErbB-2 reduced the secreted level of PSA. The inhibition of ErbB-2 or mitogen-activated 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.

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Abbreviations

PAcP:

prostatic acid phosphatase

PSA:

prostate-specific antigen

FBS:

fetal bovine serum

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

Ab:

antibody

ECL:

enhanced chemiluminescence

AR:

androgen receptor

IgG:

immunoglobulin G

HA:

hemagglutinin

MEK:

MAP kinase/ERK kinase

ERK:

extracellular signal-regulated kinase

MAP kinases:

microtubule-associated protein kinases or mitogen-activated protein kinases

p-Tyr:

phosphotyrosine

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Acknowledgements

We thank Dr Hsing-Jien Kung at the University of California Davis Cancer Center for the kind gifts of ErbB-2 and EGFR cDNAs, as well as the scFv5R cDNA- and pcDNA-transfected LNCaP cells; Dr Robert E Lewis at the University of Nebraska Medical Center for his gift of an anti-Myc Ab (9E10); Dr Stanislav Zelivianski for his helpful discussion; and Mr Michael Demapan and Ms Jamie S Lin for technical assistance. This study was supported in part by NIH grant CA88184, Nebraska Department of Health and Human Services Eppley Cancer Center LB595, National Kidney Foundation of Nebraska, and a Presidential Fellowship from the University of Nebraska.

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  1. Tsukasa Igawa

    Present address: Department of Urology, Nagasaki University School of Medicine, Sakamoto 1-7-1, Nagasaki, 852-8501, Japan

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, 68198, NE, USA

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

  2. Section of Urologic Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, 68198, NE, USA

    Ming-Fong Lin

  3. Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, 68198, NE, USA

    Ming-Fong Lin

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Lee, MS., Igawa, T., Yuan, TC. et al. ErbB-2 signaling is involved in regulating PSA secretion in androgen-independent human prostate cancer LNCaP C-81 cells. Oncogene 22, 781–796 (2003). https://doi.org/10.1038/sj.onc.1206066

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