title: Membrane androgen receptor activation induces apoptotic regression of human prostate cancer cells in vitro and in vivo.
abstract: Nongenomic androgen actions imply mechanisms different from the classical intracellular androgen receptor (iAR) activation. We have recently reported the identification of a membrane androgen receptor (mAR) on LNCaP human prostate cancer cells, mediating testosterone signal transduction within minutes. In the present study we provide evidence that activation of mAR by nonpermeable, BSA-coupled testosterone results in 1) inhibition of LNCaP cell growth (with a 50% inhibitory concentration of 5.08 nM, similar to the affinity of testosterone for membrane sites); 2) induction in LNCaP cells of both apoptosis and the proapoptotic Fas protein; and 3) a significant decrease in migration, adhesion, and invasion of iAR-negative DU145 human prostate cancer cells. These actions persisted in the presence of antiandrogen flutamide or after decreasing the content of iAR in LNCaP cells by iAR antisense oligonucleotides. Testosterone-BSA was also effective in inducing apoptosis of DU145 human prostate cancer cells, negative for iAR, but expressing mAR sites. In LNCaP cell-inoculated nude mice, treatment with testosterone-BSA (4.8 mg/kg body weight) for 1 month resulted in a 60% reduction of tumor size compared with that in control animals receiving only BSA, an effect that was not affected by the antiandrogen flutamide. Our findings suggest that activators of mAR may represent a new class of antitumoral agents of prostate cancer.
authors.affiliation: Laboratory of Experimental Endocrinology, University of Crete School of Medicine, P.O. Box 2208, Heraklion GR-71003, Greece.
authors.forename: Anastassia
authors.initials: A
authors.lastname: Hatzoglou
authors.forename: Marilena
authors.initials: M
authors.lastname: Kampa
authors.forename: Christina
authors.initials: C
authors.lastname: Kogia
authors.forename: Ioannis
authors.initials: I
authors.lastname: Charalampopoulos
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Theodoropoulos
authors.forename: Ploutarchos
authors.initials: P
authors.lastname: Anezinis
authors.forename: Constantina
authors.initials: C
authors.lastname: Dambaki
authors.forename: Evangelia A
authors.initials: EA
authors.lastname: Papakonstanti
authors.forename: Efstathios N
authors.initials: EN
authors.lastname: Stathopoulos
authors.forename: Christos
authors.initials: C
authors.lastname: Stournaras
authors.forename: Achille
authors.initials: A
authors.lastname: Gravanis
authors.forename: Elias
authors.initials: E
authors.lastname: Castanas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D012710:Serum Albumin, Bovine; D013739:Testosterone / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D020319:Oligodeoxyribonucleotides, Antisense; D011944:Receptors, Androgen; D012710:Serum Albumin, Bovine; D013739:Testosterone