title: Discovery of protein disulfide isomerase P5 inhibitors that reduce the secretion of MICA from cancer cells.
abstract: In order to regulate the activity of P5, which is a member of the protein disulfide isomerase family, we screened a chemical compound library for P5-specific inhibitors, and identified two candidate compounds (anacardic acid and NSC74859). Interestingly, anacardic acid inhibited the reductase activity of P5, but did not inhibit the activity of protein disulfide isomerase (PDI), thiol-disulfide oxidoreductase ERp57, or thioredoxin. NSC74859 inhibited all these enzymes. When we examined the effects of these compounds on the secretion of soluble major histocompatibility complex class-I-related gene A (MICA) from cancer cells, anacardic acid was found to decrease secretion. In addition, anacardic acid was found to reduce the concentration of glutathione up-regulated by the anticancer drug 17-demethoxygeldanamycin in cancer cells. These results suggest that anacardic acid can both inhibit P5 reductase activity and decrease the secretion of soluble MICA from cancer cells. It might be a novel and potent anticancer treatment by targeting P5 on the surface of cancer cells.
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, 606-8501 (Japan).
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Horibe
authors.forename: Aya
authors.initials: A
authors.lastname: Torisawa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Okuno
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000636:Aminosalicylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D048729:Anacardic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000636:Aminosalicylic Acids; D048729:Anacardic Acids; D001557:Benzenesulfonates; D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; C520337:NSC 74859; C088115:anacardic acid; C526506:PDIA5 protein, human; D019704:Protein Disulfide-Isomerases
keywords: CXXC motif; P5; inhibitors; protein disulfide isomerases; protein folding; small-molecule inhibitors