TY - JOUR
T1 - Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells.
AU - Zhang, Xiu Qing
AU - Kondrikov, Dmitry
AU - Yuan, Ta Chun
AU - Lin, Fen Fen
AU - Hansen, Joel
AU - Lin, Ming Fong
N1 - Funding Information:
We thank Dr Tony Hunter at the Salk Institute for the murine RPTPa cDNA encoding the wild-type and the mutant proteins and its Ab, and Dr Parmender P Mehta at UNMC for providing Alexa 594-conjugated goat anti-mouse IgG. We also thank the fluorescent microscope core facility at the Department of Surgery, the confocal microscope core facility at the Department of Biochemistry and Molecular Biology, and the lab colleagues for their helpful suggestions and discussions. This work was supported in part by NCI CA72274 and CA88184 from the National Institutes of Health, Nebraska Department of Health/Eppley Cancer Center LB595, and the UNMC College of Medicine Research Grant Award.
PY - 2003/10/2
Y1 - 2003/10/2
N2 - The neuroendocrine (NE) cells represent the third cell population in the normal prostate. Results of several clinical studies strongly indicate that the NE cell population is greatly increased in prostate carcinomas during androgen ablation therapy that correlates with hormone-refractory growth and poor prognosis. However, the mechanism of NE cell enrichment in prostate carcinoma remains an enigma. We investigated the molecular mechanism by which androgen-sensitive C-33 LNCaP human prostate cancer cells become NE-like cells in an androgen-reduced environment, mimicking clinical phenomenon. In the androgen-depleted condition, androgen-sensitive C-33 LNCaP cells gradually acquired the NE-like morphology and expressed an increased level of neuron-specific enolase (NSE), a classical marker of neuronal cells. Several NE-like subclone cells were established. Biochemical characterizations of these subclone cells showed that receptor-type protein-tyrosine phosphatase alpha (RPTPalpha) is elevated and ERK is constitutively activated, several folds higher than that in parental cells. In androgen-depleted condition, PD98059, an MEK inhibitor, could efficiently block not only the activation of ERK, but also the acquisition of the NE-like morphology and the elevation of NSE in C-33 LNCaP cells. In RPTPalpha cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE was elevated. In those cells in the presence of PD98059, the ERK activation and NSE elevation were abolished, following a dose-response fashion. Additionally, in constitutively active MEK mutant cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE level was elevated, and cells obtained the NE-like phenotype. Our data collectively indicated that RPTPalpha signaling via ERK is involved in the NE transdifferentiation of androgen-sensitive C-33 LNCaP human prostate cancer cells in the androgen-depleted condition.
AB - The neuroendocrine (NE) cells represent the third cell population in the normal prostate. Results of several clinical studies strongly indicate that the NE cell population is greatly increased in prostate carcinomas during androgen ablation therapy that correlates with hormone-refractory growth and poor prognosis. However, the mechanism of NE cell enrichment in prostate carcinoma remains an enigma. We investigated the molecular mechanism by which androgen-sensitive C-33 LNCaP human prostate cancer cells become NE-like cells in an androgen-reduced environment, mimicking clinical phenomenon. In the androgen-depleted condition, androgen-sensitive C-33 LNCaP cells gradually acquired the NE-like morphology and expressed an increased level of neuron-specific enolase (NSE), a classical marker of neuronal cells. Several NE-like subclone cells were established. Biochemical characterizations of these subclone cells showed that receptor-type protein-tyrosine phosphatase alpha (RPTPalpha) is elevated and ERK is constitutively activated, several folds higher than that in parental cells. In androgen-depleted condition, PD98059, an MEK inhibitor, could efficiently block not only the activation of ERK, but also the acquisition of the NE-like morphology and the elevation of NSE in C-33 LNCaP cells. In RPTPalpha cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE was elevated. In those cells in the presence of PD98059, the ERK activation and NSE elevation were abolished, following a dose-response fashion. Additionally, in constitutively active MEK mutant cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE level was elevated, and cells obtained the NE-like phenotype. Our data collectively indicated that RPTPalpha signaling via ERK is involved in the NE transdifferentiation of androgen-sensitive C-33 LNCaP human prostate cancer cells in the androgen-depleted condition.
KW - Androgen ablation
KW - ERK/MAPK
KW - Neuroendocrine differentiation
KW - Prostate cancer
KW - Receptor protein tyrosine phosphatase alpha
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U2 - 10.1038/sj.onc.1206764
DO - 10.1038/sj.onc.1206764
M3 - Article
C2 - 14555984
AN - SCOPUS:0242690301
SN - 0950-9232
VL - 22
SP - 6704
EP - 6716
JO - Oncogene
JF - Oncogene
IS - 43
ER -
