title: Docosahexaenoic Acid-mediated Inhibition of Heat Shock Protein 90-p23 Chaperone Complex and Downstream Client Proteins in Lung and Breast Cancer.
abstract: The molecular chaperone, heat shock protein 90 (Hsp90), is a critical regulator for the proper folding and stabilization of several client proteins, and is a major contributor to carcinogenesis. Specific Hsp90 inhibitors have been designed to target the ATP-binding site in order to prevent Hsp90 chaperone maturation. The current study investigated the effects of docosahexaenoic acid (DHA; C22:6 n-3) on Hsp90 function and downstream client protein expression. In vitro analyses of BT-474 human breast carcinoma and A549 human lung adenocarcinoma cell lines revealed dose-dependent decreases in intracellular ATP levels by DHA treatment, resulting in a significant reduction of Hsp90 and p23 association in both cell lines. Attenuation of the Hsp90-p23 complex led to the inhibition of Hsp90 client proteins, epidermal growth factor receptor 2 (ErbB2), and hypoxia-inducible factor 1α (HIF-1α). Similar results were observed when employing 2-deoxyglucose (2-DG), confirming that DHA and 2-DG, both independently and combined, can disturb Hsp90 molecular chaperone function. In vivo A549 xenograft analysis also demonstrated decreased expression levels of Hsp90-p23 association and diminished protein levels of ErbB2 and HIF-1α in mice supplemented with dietary DHA. These data support a role for dietary intervention to improve cancer therapy in tumors overexpressing Hsp90 and its client proteins.
authors.affiliation: a Department of Biochemistry and Molecular Biology , University of Nevada , Reno , NV , USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mouradian
authors.affiliation: a Department of Biochemistry and Molecular Biology , University of Nevada , Reno , NV , USA.
authors.forename: Irvin V
authors.initials: IV
authors.lastname: Ma
authors.affiliation: a Department of Biochemistry and Molecular Biology , University of Nevada , Reno , NV , USA.
authors.forename: Erika D
authors.initials: ED
authors.lastname: Vicente
authors.affiliation: a Department of Biochemistry and Molecular Biology , University of Nevada , Reno , NV , USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Kikawa
authors.affiliation: a Department of Biochemistry and Molecular Biology , University of Nevada , Reno , NV , USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Pardini
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D004281:Docosahexaenoic Acids; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D000071876:Prostaglandin-E Synthases; D018719:Erb-b2 Receptor Tyrosine Kinases; C497442:HIF1A protein, human; C508053:ERBB2 protein, human; C490849:PTGES3 protein, human