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Molecular and Cellular Biology, December 2001, p. 8471-8482, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8471-8482.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Interleukin-6- and Cyclic AMP-Mediated Signaling Potentiates Neuroendocrine Differentiation of LNCaP Prostate Tumor Cells

Paul D. Deeble, Daniel J. Murphy, Sarah J. Parsons, and Michael E. Cox*

Department of Microbiology and Cancer Center, University of Virginia School of Medicine, Charlottesville, Virginia

Received 14 December 2000/Returned for modification 30 January 2001/Accepted 14 September 2001

Neuroendocrine (NE) differentiation in prostatic adenocarcinomas has been reported to be an early marker for development of androgen independence. Secretion of mitogenic peptides from nondividing NE cells is thought to contribute to a more aggressive disease by promoting the proliferation of surrounding tumor cells. We undertook studies to determine whether the prostate cancer cell line LNCaP could be induced to acquire NE characteristics by treatment with agents that are found in the complex environment in which progression of prostate cancer towards androgen independence occurs. We found that cotreatment of LNCaP cells with agents that signal through cyclic AMP-dependent protein kinase (PKA), such as epinephrine and forskolin, and with the cytokine interleukin-6 (IL-6) promoted the acquisition of an NE morphological phenotype above that seen with single agents. Convergent IL-6 and PKA signaling also resulted in potentiated mitogen-activated protein kinase (MAPK) activation without affecting the level of signal transducer and activator of transcription or PKA activation observed with these agents alone. Cotreatment with epinephrine and IL-6 synergistically increased c-fos transcription as well as transcription from the beta 4 nicotinic acetylcholine receptor subunit promoter. Potentiated transcription from these elements was shown to be dependent on the MAPK pathway. Most importantly, cotreatment with PKA activators and IL-6 resulted in increased secretion of mitogenic neuropeptides. These results indicate that PKA and IL-6 signaling participates in gene transcriptional changes that reflect acquisition of an NE phenotype by LNCaP cells and suggest that similar signaling mechanisms, particularly at sites of metastasis, may be responsible for the increased NE content of many advanced prostate carcinomas.

* Corresponding author. Present address: The Prostate Center at Vancouver General Hospital, Vancouver, British Columbia V6H 3Z6, Canada. Phone: (604) 875-4818. Fax: (604) 875-5654. E-mail: mcox{at}interchange.ubc.ca.

Molecular and Cellular Biology, December 2001, p. 8471-8482, Vol. 21, No. 24
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.24.8471-8482.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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