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.