Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells

Abstract

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.

Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells

“…The treatments of some anticancer agents, such as jolkinolide B and silibinin, are also reported to be correlated with the induction of NE differentiation in LNCaP cells (Zi & Agarwal 1999, Liu et al 2002a. The data collectively support the notion that NE differentiation of PCa cells is mediated by multiple signal pathways, in part due to the heterogeneity of PCa cells (Zelivianski et al 2001 (Zhang et al 2003, Yuan et al 2006. Importantly, these NE-like LNCaP subclone cells share the same genetic profile with AS LNCaP parental cells (Yuan et al 2006), corresponding to the observation that NE-like PCa cells in tumor lesions have essentially identical genetic profiles with adjacent exocrine PCa cells (Sauer et al 2006).…”

“…Furthermore, addition of androgens abolishes steroid depletion-induced RPTPa elevation, while Casodex can compete out androgen effects and restores RPTPa as well as NSE expression (Zhang et al 2003). Further studies show that even in the regular culture condition containing androgenic activity, increased expression of RPTPa by cDNA transfection in AS LNCaP cells results in elevated levels of multiple NE markers, including NSE, chromogranin A (CgA), CgB, parathyroid hormone-related protein (PTHrP), and NT as well as acquired NE-like phenotype, suggesting a role of RPTPa in NE differentiation of AS PCa cells (Zhang et al 2003, Yuan et al 2006.…”

“…The molecular mechanism of RPTPa-induced NE differentiation in AS PCa cells is closely associated with the activation of c-Src and ERK/MAPK (Zhang et al 2003, Yuan et al 2006. This notion is supported by observations that elevated RPTPa expression in LNCaP cells leads to c-Src activation, while the expression of Y789F-RPTPa, a mutant of RPTPa which is devoid of interaction with c-Src, does not have an effect on c-Src activation and fails to induce NE marker expression as well as NE-like morphology (Yuan et al 2006).…”

“…This notion is supported by observations that elevated RPTPa expression in LNCaP cells leads to c-Src activation, while the expression of Y789F-RPTPa, a mutant of RPTPa which is devoid of interaction with c-Src, does not have an effect on c-Src activation and fails to induce NE marker expression as well as NE-like morphology (Yuan et al 2006). Similarly, increased RPTPa expression in LNCaP cells also leads to ERK/ MAPK activation, correlating with elevated expression of multiple NE markers, while this RPTPa-effect is abolished by PD98059, an MEK inhibitor (Zhang et al 2003, Yuan et al 2006. Importantly, PP2, an inhibitor of c-Src family kinases, can effectively abolish RPTPa-induced ERK/MAPK activation as well as NE marker expression, and thus blocks SR medium-induced NE-like morphology in LNCaP cells (Yuan et al 2006).…”

“…3; Zhang et al 2003, Yuan et al 2006. We further compared our NE-like LNCaP subclone cells with NCI-H660 cells, a prostatic small cell carcinoma cell line (Johnson et al 1989).…”