Vitamin D receptor agonists induce prostatic acid phosphatase to reduce cell growth and HER-2 signaling in LNCaP-derived human prostate cancer cells.
We have previously shown that concentrations of 1alpha,25-dihydroxyvitamin D(3) (1,25D) that induce G(0)/G(1) cell cycle arrest in androgen-dependent LNCaP prostate cancer cells also decrease expression of c-Myc, a proto-oncogene that stimulates progression from G(1) to S phase of the cell cycle. Since both c-Myc expression and cell cycle progression are regulated by tyrosine kinase activation, we examined the ability of 1,25D to alter tyrosine kinase signaling in LNCaP cells and the androgen-independent LNCaP C81 (C81 LN) cell line. 1,25D selectively reduced protein tyrosine phosphorylation within both the LNCaP and C81 LN cells. This reduction in tyrosine kinase signaling appears to result from elevated levels of cellular prostatic acid phosphatase (PAcP). Western blots and biochemical assays revealed 1,25D increases the level of active PAcP in both cell lines. In addition, 1,25D decreased tyrosine phosphorylation of HER-2, an EGFR family member inactivated by PAcP, and the HER-2 downstream adaptor protein p52 Shc in C81 LN cells. Inhibition of HER-2 signaling by AG825 reduces growth of C81 LN cells and the parental LNCaP cells. These data therefore suggest that 1,25D-mediated decreases in LNCaP and C81 LN cell growth are in part due to decreases in tyrosine kinase signaling that result from up-regulation of PAcP.
Stewart
LaMonica V
LV
Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Lyles
Besstina
B
Lin
Ming-Fong
MF
Weigel
Nancy L
NL
D000135:Acid Phosphatase; D002117:Calcitriol / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000096:biosynthesis / Q000378:metabolism; D019000:Phosphotyrosine / Q000032:analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects*; D014807:Vitamin D / Q000378:metabolism / Q000494:pharmacology; D020687:cdc25 Phosphatases / Q000096:biosynthesis
D000135:Acid Phosphatase; D002117:Calcitriol; D009842:Oligopeptides; D019000:Phosphotyrosine; D017027:Protein Tyrosine Phosphatases; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D018167:Receptors, Calcitriol; D014807:Vitamin D; D020687:cdc25 Phosphatases; C000715470:MAS1 protein, human; C047135:protein C activator peptide; C428439:prostatic acid phosphatase; C517004:CDC25A protein, human