The role of c‐Jun and c‐Fos expression in androgen‐independent prostate cancer

Molecular mechanisms underlying the development of androgen‐insensitive prostate cancer (AIPC) are poorly understood. However, there is growing evidence that different molecular profiles may result in the development of AIPC. Cell line studies demonstrate that c‐Jun and c‐Fos, via formation of the transcription factor activated protein 1 (AP‐1), activate androgen‐regulated genes independent of androgens and that c‐Jun alone acts as an androgen receptor co‐factor. The aim of this study was to investigate whether increased levels of c‐Jun and phosphorylated c‐Jun are associated with the development of AIPC using clinical material. Material from a cohort of 51 patients with paired tumours, obtained before and after the development of AIPC, and with full clinical biochemical follow‐up, was retrieved from the archives. Tumour c‐Jun, activated c‐Jun, c‐Fos, and pan protein kinase C (PKC) protein expression were analysed by immunohistochemistry and protein expression was scored by two independent observers using a weighted histoscore. No evidence was found to suggest that c‐Jun acting as an androgen receptor co‐factor influences the development of AIPC. However, it was observed that patients with high expression levels of phosphorylated c‐Jun had a significantly shorter survival from relapse compared with patients with low phosphorylated c‐Jun protein expression (p = 0.023), suggesting that increased AP‐1 levels may promote AIPC tumour growth. Whilst PKC did not appear to activate c‐Jun in vivo, increased PKC expression in AIPC tumours was also associated with decreased patient survival from time of relapse (p = 0.014). In conclusion, the data support the hypothesis that activation of c‐Jun plays a role in the development of AIPC via AP‐1 formation in some patients. However, PKC appears to promote the development of AIPC independently of c‐Jun activation via an as yet unexplained mechanism. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[1]  E. Baldi,et al.  The androgen receptor and prostate cancer invasion , 2006, Molecular and Cellular Endocrinology.

[2]  E. Maioli,et al.  Protein kinase C: a target for anticancer drugs? , 2004, Endocrine-related cancer.

[3]  J. Bartlett,et al.  Gene amplifications associated with the development of hormone-resistant prostate cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  Teruhiko Fujii,et al.  Protein Kinase C Promotes Apoptosis in LNCaP Prostate Cancer Cells through Activation of p38 MAPK and Inhibition of the Akt Survival Pathway* , 2003, Journal of Biological Chemistry.

[5]  K. Grigor,et al.  Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer , 2003, British Journal of Cancer.

[6]  Mitsutoshi Nakamura,et al.  Requirement of c‐jun for testosterone‐induced sensitization to N‐(4‐hydroxyphenyl)retinamide–induced apoptosis , 2003, Molecular carcinogenesis.

[7]  J. Trachtenberg,et al.  Looking to the Future: Advances in the Management of Hormone-Refractory Prostate Cancer , 2002 .

[8]  J. Shabanowitz,et al.  Androgen Receptor Phosphorylation REGULATION AND IDENTIFICATION OF THE PHOSPHORYLATION SITES* , 2002 .

[9]  Shaoyong Chen,et al.  c-Jun Potentiates the Functional Interaction between the Amino and Carboxyl Termini of the Androgen Receptor* , 2001, The Journal of Biological Chemistry.

[10]  D. Feldman,et al.  The development of androgen-independent prostate cancer , 2001, Nature Reviews Cancer.

[11]  M. Milowsky,et al.  Neutral endopeptidase inhibits neuropeptide-mediated transactivation of the insulin-like growth factor receptor-Akt cell survival pathway. , 2001, Cancer research.

[12]  Jinhua Lu,et al.  Ligand- and Coactivator-mediated Transactivation Function (AF2) of the Androgen Receptor Ligand-binding Domain Is Inhibited by the Cognate Hinge Region* , 2001, The Journal of Biological Chemistry.

[13]  E. Wagner,et al.  Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation , 2000, Oncogene.

[14]  N. Bruchovsky,et al.  Prostate cancer: molecular biology of early progression to androgen independence. , 1999, Endocrine-related cancer.

[15]  N. Engedal,et al.  CREB Binding Protein Is a Coactivator for the Androgen Receptor and Mediates Cross-talk with AP-1* , 1998, The Journal of Biological Chemistry.

[16]  M. Birrer,et al.  Identification of domains of c-Jun mediating androgen receptor transactivation , 1998, Oncogene.

[17]  M. Gleave,et al.  Androgenic Induction of Prostate-specific Antigen Gene Is Repressed by Protein-Protein Interaction between the Androgen Receptor and AP-1/c-Jun in the Human Prostate Cancer Cell Line LNCaP* , 1997, The Journal of Biological Chemistry.

[18]  S. Wise,et al.  c-Jun Can Mediate Androgen Receptor-induced Transactivation* , 1996, The Journal of Biological Chemistry.

[19]  F. S. French,et al.  Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity , 1989, Proceedings of the National Academy of Sciences of the United States of America.