Activation of membrane androgen receptors potentiates the antiproliferative effects of paclitaxel on human prostate cancer cells.
Genomic signaling mechanisms require a relatively long time to get into action and represent the main way through which steroid hormones affect target cells. In addition, steroids may rapidly activate cellular functions by non-genomic signaling mechanisms involving membrane sites. Understanding in depth the molecular mechanisms of the non-genomic action represents an important frontier for developing new and more selective pharmacologic tools for endocrine therapies. In the present study, we report that membrane-impermeable testosterone-bovine serum albumin (BSA) acts synergistically with paclitaxel in modifying actin and tubulin cytoskeleton dynamics in LNCaP (androgen sensitive) and DU-145 (androgen insensitive) human prostate cancer cell lines. In addition, coincubation of either cell line with testosterone-BSA and paclitaxel induced inhibition of cell proliferation and apoptosis. Finally, in vivo experiments in LNCaP and DU-145 tumor xenografts in nude mice showed that both agents decrease tumor mass, whereas testosterone-BSA enhances the effect of paclitaxel. Our findings suggest that chronic activation of membrane androgen receptors in vitro and in vivo facilitates and sustains for a longer time the antitumoral action of cytoskeletal acting agents.
Kampa
Marilena
M
Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, P.O. Box 2208, Heraklion, GR-71003, Greece. castanas@med.uoc.gr
Kogia
Christina
C
Theodoropoulos
Panayiotis A
PA
Anezinis
Ploutarchos
P
Charalampopoulos
Ioannis
I
Papakonstanti
Evangelia A
EA
Stathopoulos
Efstathios N
EN
Hatzoglou
Anastassia
A
Stournaras
Christos
C
Gravanis
Achille
A
Castanas
Elias
E
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology; D013739:Testosterone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D011944:Receptors, Androgen; D012710:Serum Albumin, Bovine; D013739:Testosterone; D017239:Paclitaxel