TY - JOUR
T1 - ErbB-2 signaling is involved in regulating PSA secretion in androgen-independent human prostate cancer LNCaP C-81 cells
AU - Lee, Ming Shyue
AU - Igawa, Tsukasa
AU - Yuan, Ta Chun
AU - Zhang, Xiu Qing
AU - Lin, Fen Fen
AU - Lin, Ming Fong
N1 - Funding Information:
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.
PY - 2003/2/6
Y1 - 2003/2/6
N2 - 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.
AB - 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.
KW - Androgen independence
KW - ErbB-2
KW - MAP kinases
KW - PSA secretion
KW - Prostate cancer
KW - Prostatic acid phosphatase
KW - Protein tyrosine kinase
KW - Protein tyrosine phosphatase
UR - http://www.scopus.com/inward/record.url?scp=0037421969&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037421969&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1206066
DO - 10.1038/sj.onc.1206066
M3 - Article
C2 - 12569372
AN - SCOPUS:0037421969
SN - 0950-9232
VL - 22
SP - 781
EP - 796
JO - Oncogene
JF - Oncogene
IS - 5
ER -