title: Modulation of the estrogen-regulated proteins cathepsin D and pS2 by opioid agonists in hormone-sensitive breast cancer cell lines (MCF7 and T47D): evidence for an interaction between the two systems.
abstract: In many cancer cell lines, including breast, prostate, lung, brain, head and neck, retina, and the gastrointestinal tract, opioids decrease cell proliferation in a dose-dependent and reversible manner. Opioid and/or other neuropeptide receptors mediate this decrease. We report that only the steroid-hormone-sensitive cell lines MCF7 and T47D respond to opioid growth inhibition in a dose-dependent manner. Therefore, an interaction of the opioid and steroid receptor system might exist, as is the case with insulin. To investigate this interaction, we have assayed two estrogen-inducible proteins (pS2 and the lysosomal enzyme cathepsin D) in MCF7 and T47D cells. When cells were grown in the presence of FBS (in which case a minimal quantity of estrogens and/or opioids is provided by the serum), we observed either no effect of etorphine or ethylketocyclazocine (EKC) or an increase of secretion and/or production of pS2 and cathepsin D. However, when cells were cultured in charcoal-stripped serum and in the absence of phenol red, the effect of the two opioids is different: EKC decreased the production and/or secretion of pS2 and cathepsin D, whereas etorphine increased their synthesis and/or secretion. The differential effect of the two general opioids was attributed to their different receptor selectivity. Furthermore, the variations of the ratio of secreted/produced protein and the use of cycloheximide indicate that opioids selectively modify the regulatory pathway of each protein discretely. In conclusion, through the interaction with opioid and perhaps other membrane-receptor sites, opioid agonists modify in a dose-dependent manner the production and the secretion of two estrogen-regulated proteins. Opioids may therefore disturb hormonal signals mediated by the estrogen receptors. Hence, these chemicals may have potential endocrine disrupting activities.
authors.affiliation: Laboratoire de Cancerologie Expérimentale, CJF-INSERM 93-11, Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Panagiotou
authors.forename: A
authors.initials: A
authors.lastname: Hatzoglou
authors.forename: F
authors.initials: F
authors.lastname: Calvo
authors.forename: P M
authors.initials: PM
authors.lastname: Martin
authors.forename: E
authors.initials: E
authors.lastname: Castanas
mesh_terms: D001943:Breast Neoplasms; D002402:Cathepsin D / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004174:Diprenorphine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D016314:Ethylketocyclazocine / Q000494:pharmacology; D005048:Etorphine / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000819:agonists / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D011500:Protein Synthesis Inhibitors; D011506:Proteins; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D004174:Diprenorphine; D005048:Etorphine; D004958:Estradiol; D016314:Ethylketocyclazocine; D003513:Cycloheximide; D002402:Cathepsin D