Androgen-sensitive prostate cancer is characterized by a lower malignant potentialDepartment of Clinical Physiopathology University of Florence Viale Pieraccini 6 I-50134 Florence, Italy
Emerging evidence indicate that androgen-sensitive prostate cancer is characterized by a lower malignant potential. We previously demonstrated that androgen receptor (AR) expression by transfection of an androgen-independent prostate cancer cell line (PC3) decreases Matrigel invasion and laminin adhesion of these cells through negative modulation of 64 expression. Treatment with the synthetic androgen R1881 further reduced adhesion and invasion of PC3-AR cells without however modifying 64 expression. We investigated here if the AR, upon activation by androgens, has a direct effect on 64-EGF receptor (EGF-R) interaction and intracellular signaling leading to invasion and migration of these cells. Immunoconfocal microscopy demonstrated that in control cells transfected only with the vector (PC3-Neo cells), 64 and EGF-R co-localized and redistribute at the plasma membrane in response to EGF. In PC3-AR cells co-localization between the two molecules was strongly reduced and completely abolished by pre-treatment with R1881. Co-immunoprecipitation studies confirmed the physical interaction between EGF-R and a6b4. Interestingly, tyrosine phosphorylation of b4 subunit and EGF-R autophoshorylation in response to EGF treatment were reduced in PC3-AR cells. To determine whether disruption of EGF-R-a6b4 interaction and signaling in PC3-AR cells was due to a direct action of the AR on the molecular complex, immunoconfocal and co-immunoprecipitation studies of EGF-R and AR were conducted. These studies showed co-localization at membrane level as well as co-immunoprecipitation of the two proteins, indicating an interaction of EGF-R and a6b4. PI3K activity, a key signaling pathway for invasion, was decreased both in basal conditions and in response to EGF in PC3-AR cells and was further reduced by treatment with R1881. In conclusion, in androgen-sensitive PC3 cells, androgens and AR contribute to confer a less malignant phenotype both by reducing the expression of a6b4 and by interfering with EGF-R-a6b4 interaction and signaling leading to invasion through a direct interaction between AR and EGF-R.
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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Predictive Markers.