Suppression of LNCaP prostate cancer xenograft tumors by a prostate-specific protein tyrosine phosphatase, prostatic acid phosphatase.
BACKGROUND
Although the molecular mechanism of androgen-independent prostate cancer growth and progression has been gradually elucidated, there is limited effective treatment for this prevalent disease. Human prostatic acid phosphatase (PAcP), a major protein tyrosine phosphatase in prostate epithelium, plays a critical role in regulating the growth of prostate cancer cells. In prostate carcinomas, the expression of cellular PAcP decreases. To explore directly the possible therapeutic potential of cellular PAcP, we investigated the suppression effect of PAcP by utilizing cDNA direct intratumoral administration in androgen-independent LNCaP xenograft tumors.


METHODS
An androgen-independent LNCaP cell model (C-33 and C-81 cells) and stable subclones of PAcP cDNA-transfected C-81 cells (LNCaP-23 and LNCaP-34 cells) were used for the experiments. We examined the growth property and expression of PAcP and c-ErbB-2 of these different LNCaP cells in vitro and in vivo. We subsequently investigated the growth suppression effect of PAcP cDNA intratumoral injection in pre-established C-81 xenograft tumors, and analyzed the expression of PAcP, prostate-specific antigen (PSA), proliferating cell nuclear antigen (PCNA), and c-ErbB-2 in the tumors by immunohistochemistry and Western blotting.


RESULTS
The different LNCaP cells exhibited different growth property and tumorigenicity, both in cell culture and xenograft. Biochemical characterizations revealed that the level of cellular PAcP correlated negatively with the growth property of different LNCaP cells, while the level of tyrophosphorylated c-ErbB-2 had an inverse correlation with cellular PAcP. The single intratumoral administration of the wild type PAcP cDNA showed a significant suppression effect on C-81 xenograft tumor growth, compared to vector alone-injected control (P<0.05). In the tumors injected with this PAcP cDNA, the PAcP expression was detected 1 week (wk) after injection, but was undetectable at 6 wk, which inversely correlated with the level of tyrophosphorylated c-ErbB-2 and the degree of cell proliferation indicated by PCNA staining.


CONCLUSIONS
Our results clearly demonstrated that cellular PAcP has a suppression effect on the growth of androgen-independent LNCaP xenograft tumors. This effect occurs at least partly through the dephosphorylation of c-ErbB-2 by PAcP, the prostate-specific protein tyrosine phosphatase. The data indicates that human PAcP could be utilized in the corrective gene therapy for a subgroup of androgen-independent human prostate cancer cells that lack cellular PAcP expression.
Igawa
Tsukasa
T
Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-4525, USA.
Lin
Fen-Fen
FF
Rao
Prathibha
P
Lin
Ming-Fong
MF
D000135:Acid Phosphatase; D000818:Animals; D002455:Cell Division / Q000502:physiology; D004247:DNA / Q000008:administration & dosage / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018809:Proliferating Cell Nuclear Antigen; D004247:DNA; D066246:ErbB Receptors; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases; D017430:Prostate-Specific Antigen