title: Aromatase destabilizer: novel action of exemestane, a food and drug administration-approved aromatase inhibitor.
abstract: Using Western blot as the major technique, we studied the effects of the three Food and Drug Administration (FDA)-approved aromatase inhibitors (AI) on aromatase protein stability in the aromatase-overexpressing breast cancer cell line MCF-7aro. We have found that exemestane treatment significantly reduces aromatase protein level. Exemestane induces aromatase degradation in a dose-responsive manner (25-200 nmol/L), and the effect can be seen in as early as 2 hours. Metabolic labeling with S(35)-methionine was used to determine the half-life (t(1/2)) of aromatase protein. In the presence of 200 nmol/L exemestane, the t(1/2) of aromatase was reduced to 12.5 hours from 28.2 hours in the untreated cells. Furthermore, exemestane-induced aromatase degradation can be completely blocked by 10 micromol/L MG132, indicating that the degradation is mediated by proteasome. We also examined the effect of exemestane on aromatase mRNA level using real-time reverse transcription-PCR. No significant changes in mRNA level were detected after 8 hours of treatment with exemestane (200 nmol/L). This is the first report on the evaluation of three FDA-approved AIs on the stability of the aromatase protein. We have found that exemestane, different from letrozole and anastrozole, can destabilize the aromatase protein.
authors.affiliation: Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D000735:Androstenedione / Q000031:analogs & derivatives / Q000494:pharmacology; D001141:Aromatase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004795:Enzyme Stability / Q000187:drug effects; D005260:Female; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000502:physiology
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D000735:Androstenedione; D001141:Aromatase; D046988:Proteasome Endopeptidase Complex; C056516:exemestane; C014594:formestane