title: Aldo-keto reductase 1B10 promotes development of cisplatin resistance in gastrointestinal cancer cells through down-regulating peroxisome proliferator-activated receptor-γ-dependent mechanism.
abstract: Cisplatin (cis-diamminedichloroplatinum, CDDP) is one of the most effective chemotherapeutic drugs that are used for treatment of patients with gastrointestinal cancer cells, but its continuous administration often evokes the development of chemoresistance. In this study, we investigated alterations in antioxidant molecules and functions using a newly established CDDP-resistant variant of gastric cancer MKN45 cells, and found that aldo-keto reductase 1B10 (AKR1B10) is significantly up-regulated with acquisition of the CDDP resistance. In the nonresistant MKN45 cells, the sensitivity to cytotoxic effect of CDDP was decreased and increased by overexpression and silencing of AKR1B10, respectively. In addition, the AKR1B10 overexpression markedly suppressed accumulation and cytotoxicity of 4-hydroxy-2-nonenal that is produced during lipid peroxidation by CDDP treatment, suggesting that the enzyme acts as a crucial factor for facilitation of the CDDP resistance through inhibiting induction of oxidative stress by the drug. Transient exposure to CDDP and induction of the CDDP resistance decreased expression of peroxisome proliferator-activated receptor-γ (PPARγ) in MKN45 and colon cancer LoVo cells. Additionally, overexpression of PPARγ in the cells elevated the sensitivity to the CDDP toxicity, which was further augmented by concomitant treatment with a PPARγ ligand rosiglitazone. Intriguingly, overexpression of AKR1B10 in the cells resulted in a decrease in PPARγ expression, which was recovered by addition of an AKR1B10 inhibitor oleanolic acid, inferring that PPARγ is a downstream target of AKR1B10-dependent mechanism underlying the CDDP resistance. Combined treatment with the AKR1B10 inhibitor and PPARγ ligand elevated the CDDP sensitivity, which was almost the same level as that in the parental cells. These results suggest that combined treatment with the AKR1B10 inhibitor and PPARγ ligand is an effective adjuvant therapy for overcoming CDDP resistance of gastrointestinal cancer cells.
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: matsunagat@gifu-pu.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kezuka
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Okumura
authors.affiliation: Laboratory of Clinical Pharmacy, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iguchi
authors.affiliation: Department of Diabetes and Endocrinology, Saitama Medical University, Saitama, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Inoue
authors.affiliation: Laboratory of Pharmaceutics, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.affiliation: Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.affiliation: Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics* / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047495:PPAR gamma; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D002945:Cisplatin
keywords: Aldo-keto reductase 1B10; Chemoresistance; Cisplatin; Gastrointestinal cancer cells; Peroxisome proliferator-activated receptor-γ