The opioid agonist ethylketocyclazocine reverts the rapid, non-genomic effects of membrane testosterone receptors in the human prostate LNCaP cell line.
Neuropeptides influence cancer cell replication and growth. Opioid peptides, and opiergic neurons are found in the prostate gland, and they are proposed to exert a role in tumor regulation, influencing cancer cell growth, as opioid agonists inhibit cell growth in several systems, including the human prostate cancer cell line LNCaP. In the same cell line, the existence of membrane testosterone receptors was recently reported, which increase, in a non-genomic manner, the secretion of PSA, and modify actin cytoskeleton dynamics, through the signaling cascade FAK-->PI-3 kinase-->Cdc42/Rac1. In the present work, we present data supporting that the general opioid agonist Ethylketocyclazocine (EKC) decreases testosterone-BSA (a non-internalizable testosterone analog) induced PSA secretion. Furthermore, we report that this opioid affects this non-genomic testosterone action, by modifying the distribution of the actin cytoskeleton in the cells, disrupting the above signaling cascade. In addition, after long (>24 h) incubation, opioids decrease the number of membrane testosterone receptors, and reverse their effect on the signaling molecules. In conclusion, our results provide some new insights of a possible action of opioids in prostate cancer control by interfering with the action and the expression of membrane testosterone receptors and signaling.
Kampa
Marilena
M
Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, 71110, Heraklion, Greece.
Papakonstanti
Evangelia A
EA
Alexaki
Vassilia-Ismini
VI
Hatzoglou
Anastassia
A
Stournaras
Christos
C
Castanas
Elias
E
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D016314:Ethylketocyclazocine / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D008297:Male; D018847:Opioid Peptides / Q000819:agonists / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013739:Testosterone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000701:Analgesics, Opioid; D018847:Opioid Peptides; D011944:Receptors, Androgen; C045037:testosterone-3-carboxymethyloxime-bovine serum albumin conjugate; D012710:Serum Albumin, Bovine; D013739:Testosterone; D016314:Ethylketocyclazocine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D017430:Prostate-Specific Antigen