Previous Article | Next Article 
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
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.
This article has been cited by other articles:
-
DaSilva, J., Gioeli, D., Weber, M. J., Parsons, S. J.
(2009). The Neuroendocrine-Derived Peptide Parathyroid Hormone-Related Protein Promotes Prostate Cancer Cell Growth by Stabilizing the Androgen Receptor. Cancer Res.
69: 7402-7411
[Abstract]
[Full Text]
-
Chun, J. Y., Nadiminty, N., Dutt, S., Lou, W., Yang, J. C., Kung, H.-J., Evans, C. P., Gao, A. C.
(2009). Interleukin-6 Regulates Androgen Synthesis in Prostate Cancer Cells. Clin. Cancer Res.
15: 4815-4822
[Abstract]
[Full Text]
-
PISSIMISSIS, N., PAPAGEORGIOU, E., LEMBESSIS, P., ARMAKOLAS, A., KOUTSILIERIS, M.
(2009). The Glutamatergic System Expression in Human PC-3 and LNCaP Prostate Cancer Cells. Anticancer Res
29: 371-377
[Abstract]
[Full Text]
-
Yuan, T.-C., Veeramani, S., Lin, M.-F.
(2007). Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells. Endocr Relat Cancer
14: 531-547
[Abstract]
[Full Text]
-
Sastry, K. S. R., Karpova, Y., Prokopovich, S., Smith, A. J., Essau, B., Gersappe, A., Carson, J. P., Weber, M. J., Register, T. C., Chen, Y. Q., Penn, R. B., Kulik, G.
(2007). Epinephrine Protects Cancer Cells from Apoptosis via Activation of cAMP-dependent Protein Kinase and BAD Phosphorylation. J. Biol. Chem.
282: 14094-14100
[Abstract]
[Full Text]
-
Deeble, P. D., Cox, M. E., Frierson, H. F. Jr., Sikes, R. A., Palmer, J. B., Davidson, R. J., Casarez, E. V., Amorino, G. P., Parsons, S. J.
(2007). Androgen-Independent Growth and Tumorigenesis of Prostate Cancer Cells Are Enhanced by the Presence of PKA-Differentiated Neuroendocrine Cells. Cancer Res.
67: 3663-3672
[Abstract]
[Full Text]
-
Bellezza, I., Neuwirt, H., Nemes, C., Cavarretta, I. T., Puhr, M., Steiner, H., Minelli, A., Bartsch, G., Offner, F., Hobisch, A., Doppler, W., Culig, Z.
(2006). Suppressor of Cytokine Signaling-3 Antagonizes cAMP Effects on Proliferation and Apoptosis and Is Expressed in Human Prostate Cancer. Am. J. Pathol.
169: 2199-2208
[Abstract]
[Full Text]
-
Mitra, S., Annamalai, L., Chakraborty, S., Johnson, K., Song, X.-H., Batra, S. K., Mehta, P. P.
(2006). Androgen-regulated Formation and Degradation of Gap Junctions in Androgen-responsive Human Prostate Cancer Cells. Mol. Biol. Cell
17: 5400-5416
[Abstract]
[Full Text]
-
Best, C. J.M., Gillespie, J. W., Yi, Y., Chandramouli, G. V.R., Perlmutter, M. A., Gathright, Y., Erickson, H. S., Georgevich, L., Tangrea, M. A., Duray, P. H., Gonzalez, S., Velasco, A., Linehan, W. M., Matusik, R. J., Price, D. K., Figg, W. D., Emmert-Buck, M. R., Chuaqui, R. F.
(2005). Molecular Alterations in Primary Prostate Cancer after Androgen Ablation Therapy. Clin. Cancer Res.
11: 6823-6834
[Abstract]
[Full Text]
-
Yang, X., Chen, M.-W., Terry, S., Vacherot, F., Chopin, D. K., Bemis, D. L., Kitajewski, J., Benson, M. C., Guo, Y., Buttyan, R.
(2005). A Human- and Male-Specific Protocadherin that Acts through the Wnt Signaling Pathway to Induce Neuroendocrine Transdifferentiation of Prostate Cancer Cells. Cancer Res.
65: 5263-5271
[Abstract]
[Full Text]
-
Lemonnier, L, Lazarenko, R, Shuba, Y, Thebault, S, Roudbaraki, M, Lepage, G, Prevarskaya, N, Skryma, R
(2005). Alterations in the regulatory volume decrease (RVD) and swelling-activated Cl-current associated with neuroendocrine differentiation of prostate cancer epithelial cells. Endocr Relat Cancer
12: 335-349
[Abstract]
[Full Text]
-
Kirschner, L. S., Kusewitt, D. F., Matyakhina, L., Towns, W. H. II, Carney, J. A., Westphal, H., Stratakis, C. A.
(2005). A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP-Responsive Tissues. Cancer Res.
65: 4506-4514
[Abstract]
[Full Text]
-
Dunn, G. P., Sheehan, K. C.F., Old, L. J., Schreiber, R. D.
(2005). IFN Unresponsiveness in LNCaP Cells Due to the Lack of JAK1 Gene Expression. Cancer Res.
65: 3447-3453
[Abstract]
[Full Text]
-
George, D. J., Halabi, S., Shepard, T. F., Sanford, B., Vogelzang, N. J., Small, E. J., Kantoff, P. W.
(2005). The Prognostic Significance of Plasma Interleukin-6 Levels in Patients with Metastatic Hormone-Refractory Prostate Cancer: Results from Cancer and Leukemia Group B 9480. Clin. Cancer Res.
11: 1815-1820
[Abstract]
[Full Text]
-
Kim, J., Adam, R. M., Solomon, K. R., Freeman, M. R.
(2004). Involvement of Cholesterol-Rich Lipid Rafts in Interleukin-6-Induced Neuroendocrine Differentiation of LNCaP Prostate Cancer Cells. Endocrinology
145: 613-619
[Abstract]
[Full Text]
-
Daaka, Y.
(2004). G Proteins in Cancer: The Prostate Cancer Paradigm. Sci Signal
2004: re2-re2
[Abstract]
[Full Text]
-
Brody, J. R., Kadkol, S. S., Hauer, M. C., Rajaii, F., Lee, J., Pasternack, G. R.
(2004). pp32 Reduction Induces Differentiation of TSU-Pr1 Cells. Am. J. Pathol.
164: 273-283
[Abstract]
[Full Text]
-
DeMichele, A., Martin, A.-M., Mick, R., Gor, P., Wray, L., Klein-Cabral, M., Athanasiadis, G., Colligan, T., Stadtmauer, E., Weber, B.
(2003). Interleukin-6 -174G->C Polymorphism Is Associated with Improved Outcome in High-Risk Breast Cancer. Cancer Res.
63: 8051-8056
[Abstract]
[Full Text]
-
Laszlo, G. S., Nathanson, N. M.
(2003). Src Family Kinase-independent Signal Transduction and Gene Induction by Leukemia Inhibitory Factor. J. Biol. Chem.
278: 27750-27757
[Abstract]
[Full Text]
-
Steiner, H., Godoy-Tundidor, S., Rogatsch, H., Berger, A. P., Fuchs, D., Comuzzi, B., Bartsch, G., Hobisch, A., Culig, Z.
(2003). Accelerated in Vivo Growth of Prostate Tumors that Up-Regulate Interleukin-6 Is Associated with Reduced Retinoblastoma Protein Expression and Activation of the Mitogen-Activated Protein Kinase Pathway. Am. J. Pathol.
162: 655-663
[Abstract]
[Full Text]
-
Lee, S. O., Lou, W., Hou, M., de Miguel, F., Gerber, L., Gao, A. C.
(2003). Interleukin-6 Promotes Androgen-independent Growth in LNCaP Human Prostate Cancer Cells. Clin. Cancer Res.
9: 370-376
[Abstract]
[Full Text]