title: Pathophysiological roles of aldo-keto reductases (AKR1C1 and AKR1C3) in development of cisplatin resistance in human colon cancers.
abstract: Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used for treatment of patients with solid tumors formed in various organs including the lung, prostate and cervix, but is much less sensitive in colon and breast cancers. One major factor implicated in the ineffectiveness has been suggested to be acquisition of the CDDP resistance. Here, we established the CDDP-resistant phenotypes of human colon HCT15 cells by continuously exposing them to incremental concentrations of the drug, and monitored expressions of aldo-keto reductases (AKRs) 1A1, 1B1, 1B10, 1C1, 1C2 and 1C3. Among the six AKRs, AKR1C1 and AKR1C3 are highly induced with the CDDP resistance. The resistance lowered the sensitivity toward cellular damages evoked by oxidative stress-derived aldehydes, 4-hydroxy-2-nonenal and 4-oxo-2-nonenal that are detoxified by AKR1C1 and AKR1C3. Overexpression of AKR1C1 or AKR1C3 in the parental HCT15 cells mitigated the cytotoxicity of the aldehydes and CDDP. Knockdown of both AKR1C1 and AKR1C3 in the resistant cells or treatment of the cells with specific inhibitors of the AKRs increased the sensitivity to CDDP toxicity. Thus, the two AKRs participate in the mechanism underlying the CDDP resistance probably via detoxification of the aldehydes resulting from enhanced oxidative stress. The resistant cells also showed an enhancement in proteolytic activity of proteasome accompanied by overexpression of its catalytic subunits (PSMβ9 and PSMβ10). Pretreatment of the resistant cells with a potent proteasome inhibitor Z-Leu-Leu-Leu-al augmented the CDDP sensitization elicited by the AKR inhibitors. Additionally, the treatment of the cells with Z-Leu-Leu-Leu-al and the AKR inhibitors induced the expressions of the two AKRs and proteasome subunits. Collectively, these results suggest the involvement of up-regulated AKR1C1, AKR1C3 and proteasome in CDDP resistance of colon cancers and support a chemotherapeutic role for their inhibitors.
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu, Japan. matsunagat@gifu-pu.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Aki
authors.initials: A
authors.lastname: Hojo
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamane
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000494:pharmacology; D000074425:Aldo-Keto Reductase Family 1 Member C3; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D019008:Drug Resistance, Neoplasm; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: C403894:4-oxo-2-nonenal; D000447:Aldehydes; D015096:3-Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D046988:Proteasome Endopeptidase Complex; C027576:4-hydroxy-2-nonenal; D002945:Cisplatin