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

Oncogene volume 22, pages 6704–6716 (2003)Cite this article

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 (RPTPα) 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 RPTPα 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 RPTPα signaling via ERK is involved in the NE transdifferentiation of androgen-sensitive C-33 LNCaP human prostate cancer cells in the androgen-depleted condition.

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Article 04 February 2021

Richard J. Rebello, Christoph Oing, … Robert G. Bristow

Abbreviations

NE:

neuroendocrine

NSE:

neuron-specific enolase

cAMP:

adenosine 3′,5′-cyclic monophosphate

db-cAMP:

dibutyrate cAMP

PKA:

protein kinase A

PI3K:

phosphatidylinositol 3-kinase

IL:

interleukin

ERK:

extracellular signal-regulated kinase

MEK:

ERK kinase

MAPK:

mitogen-activated protein kinase

MKP:

ERK/MAPK phosphatase

NGF:

nerve growth factor

HA:

hemagglutinin

FBS:

fetal bovine serum

SR-FBS:

steroid-reduced FBS

ECL:

enhanced chemiluminescence

GFP:

green fluorescent protein

PTP:

protein tyrosine phosphatase

RPTPα:

receptor protein tyrosine phosphatase alpha

DHT:

5α-dihydrotestosterone

Ab:

antibody

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Acknowledgements

We thank Dr Tony Hunter at the Salk Institute for the murine RPTPα 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.

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  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 984525 Nebraska Medical Center, Omaha, 68198-4525, NE, USA

    Xiu-Qing Zhang, Dmitry Kondrikov, Ta-Chun Yuan, Fen-Fen Lin, Joel Hansen & Ming-Fong Lin

  2. Department of Surgery, Section of Urologic Surgery, College of Medicine, University of Nebraska Medical Center, 984525 Nebraska Medical Center, Omaha, 68198-4525, NE, USA

    Ming-Fong Lin

  3. Eppley Cancer Institute, University of Nebraska Medical Center, 984525 Nebraska Medical Center, Omaha, 68198-4525, NE, USA

    Ming-Fong Lin

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Zhang, XQ., Kondrikov, D., Yuan, TC. et al. Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells. Oncogene 22, 6704–6716 (2003). https://doi.org/10.1038/sj.onc.1206764

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