title: Proteasome inhibitors MG-132 and bortezomib induce AKR1C1, AKR1C3, AKR1B1, and AKR1B10 in human colon cancer cell lines SW-480 and HT-29.
abstract: Aldo-keto reductases (AKRs) play central roles in the reductive metabolism of endogenous signaling molecules and in the detoxification of xenobiotics. AKRC1-1C3, AKR1B1 and AKR1B10 have been shown to be regulated via nuclear factor-erythroid 2 related factor 2 (Nrf2), a transcription factor that is activated upon oxidative stress. Proteasome inhibitors bortezomib and MG-132 produce mild oxidative stress that activates Nrf2-mediated gene expression that in turn may have cytoprotective effects. Bortezomib is clinically approved to treat haematological malignancies and it has also proven activity in solid tumors such as colon cancer. The present study investigated the effect of bortezomib and MG-132 on the expression of AKR1C1-1C4, AKR1B1, and AKR1B10 in colon cancer cell lines HT-29 and SW-480. Human cancer cell lines derived from different organs (lung, colon, pancreas, skin, liver, ovary) were initially assayed for the expression of the AKRs, showing a very unequal distribution. Even among the colon cell lines HT-29, Caco-2, HCT116 and SW-480, the AKRs were expressed quite non-uniformly. HT-29 cells expressed all AKRs on the mRNA level including liver-specific AKR1C4, but AKR1B1 was almost undetectable. In SW-480 cells, treatment with bortezomib (50 nM, 48 h) dramatically increased mRNA levels of AKR1B10 (32-fold), AKR1B1 (5.5-fold), and, to a lesser extent, AKR1C1 and AKR1C3. Drug-efflux transporter MRP2 (ABCC2) and Cox-2 were induced as well. AKR1C2 mRNA was down-regulated in SW-480 but induced in HT-29 cells. MG-132 increased mRNA amounts of AKR1C1, 1C3, 1B1, and 1B10 in a concentration-dependent manner. AKR1B10 and AKR1B1 protein expression was inducible by bortezomib in HT-29 cells, but not detectable in SW-480 cells. In conclusion, treatment with proteasome inhibitors increased the expression of several AKRs as well as of MRP2. It remains to be investigated whether this enzyme induction may contribute to enhanced cell survival and thereby supporting the phenomenon of multidrug resistance upon cancer chemotherapy.
authors.affiliation: Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Kiel, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Ebert
authors.forename: Michael
authors.initials: M
authors.lastname: Kisiela
authors.forename: Vladimir
authors.initials: V
authors.lastname: Wsól
authors.forename: Edmund
authors.initials: E
authors.lastname: Maser
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000449:Aldehyde Reductase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000074408:Aldo-Keto Reductases; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017879:Isothiocyanates; D007976:Leupeptins / Q000494:pharmacology*; D008298:Maleates / Q000494:pharmacology; D000089762:Multidrug Resistance-Associated Protein 2; D051267:NF-E2-Related Factor 2 / Q000819:agonists; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D013997:Time Factors
chemical_list: C000715087:ABCC2 protein, human; D001897:Boronic Acids; D017879:Isothiocyanates; D007976:Leupeptins; D008298:Maleates; D000089762:Multidrug Resistance-Associated Protein 2; D051267:NF-E2-Related Factor 2; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D013454:Sulfoxides; D013861:Thiocyanates; D000069286:Bortezomib; D015096:3-Hydroxysteroid Dehydrogenases; D000429:Alcohol Oxidoreductases; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D006911:Hydroxyprostaglandin Dehydrogenases; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C014476:diethyl maleate; C016766:sulforaphane; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde