Interaction between protein tyrosine phosphatase and protein tyrosine kinase is involved in androgen-promoted growth of human prostate cancer cells.
Steroid hormones play key roles in regulating cell proliferation and differentiation in targeting tissues. However, in advanced cancers, the steroid hormone regulation is frequently attenuated through a yet unknown mechanism even in the presence of functional steroid hormone receptors. We investigate the functional role of tyrosine phosphorylation signaling in the hormone-refractory growth of human prostate tumors. Initial studies demonstrate that the androgen-responsive phenotype of human prostate cancer cells associates with a low phosphotyrosine (p-Tyr) level of ErbB-2, which is regulated by cellular prostatic acid phosphatase (PAcP), a protein tyrosine phosphatase. In prostate cancer cells, the p-Tyr level, but not the protein level, of ErbB-2 inversely correlates with the androgen-responsiveness of cell proliferation. Androgen-stimulated cell growth concurs with a down-regulation of cellular PAcP, an elevated p-Tyr level of ErbB-2, and the activation of mitogen-activated protein kinases. Furthermore, only the ErbB-2 inhibitor AG 879, but not the EGFR inhibitor AG 1478, abolishes androgen-induced cell proliferation. Forced expression of ErbB-2 can also attenuate androgen promotion of cell growth. Data taken collectively conclude that in human prostate cancer cells, the tyrosine phosphorylation of ErbB-2 regulated by cellular PAcP plays a key role in regulating androgen-mediated proliferation signaling. Oncogene (2000).
Meng
T C
TC
Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, NE 68198, USA.
Lee
M S
MS
Lin
M F
MF
D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000728:Androgens; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases