Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling
- 11 October 2001
- journal article
- Published by Springer Nature in Oncogene
- Vol. 20 (46) , 6718-6723
- https://doi.org/10.1038/sj.onc.1204889
Abstract
Androgen deprivation therapy for advanced prostate cancer is often effective, but not curative. Molecular pathways mediating the therapeutic response and those contributing to the subsequent hormone-refractory cell growth remain poorly understood. Here, cDNA microarray analysis of human CWR22 prostate cancer xenografts during the course of androgen deprivation therapy revealed distinct global gene expression profiles in primary, regressing and recurrent tumors. Elucidation of the genes involved in the transition between these states implicated specific molecular mechanisms in therapy failure and tumor progression. First, we identified a set of androgen-responsive genes whose expression decreased during the therapy response, but was then systematically restored in the recurrent tumors. In addition, altered expression of genes that encode known targets of rapamycin or that converge on the PI3K/AKT/FRAP pathway was observed in the recurrent tumors. Further suggestion for the involvement of these genes in hormone-refractory prostate cancer came from the observation that cells established from the recurrent xenografts were strongly inhibited in vitro by rapamycin. The results of this functional genomic analysis suggest that the combined effect of re-expression of androgen-responsive genes as well as the activation of rapamycin-sensitive signaling may drive prostate cancer progression, and contribute to the failure of androgen-deprivation therapy.Keywords
This publication has 14 references indexed in Scilit:
- Rapid signalling by androgen receptor in prostate cancer cellsOncogene, 1999
- Hormone Therapy Failure in Human Prostate Cancer: Analysis by Complementary DNA and Tissue MicroarraysJNCI Journal of the National Cancer Institute, 1999
- Mitogen-Activated Protein Kinase Kinase Kinase 1 Activates Androgen Receptor-Dependent Transcription and Apoptosis in Prostate CancerMolecular and Cellular Biology, 1999
- Mechanistic Concepts in Androgen-dependence of Prostate CancerCancer and Metastasis Reviews, 1998
- Molecular Cloning of Human FKBP51 and Comparisons of Immunophilin Interactions with Hsp90 and Progesterone ReceptorMolecular and Cellular Biology, 1997
- CWR22 Xenograft as an Ex Vivo Human Tumor Model for Prostate Cancer Gene TherapyJNCI Journal of the National Cancer Institute, 1996
- Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian CellsJournal of Biological Chemistry, 1995
- Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progressionCell, 1993
- Xenografts of Primary Human Prostatic CarcinomaJNCI Journal of the National Cancer Institute, 1993
- Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexesCell, 1991