title: Acquisition of doxorubicin resistance facilitates migrating and invasive potentials of gastric cancer MKN45 cells through up-regulating aldo-keto reductase 1B10.
abstract: Continuous exposure to doxorubicin (DOX) accelerates hyposensitivity to the drug-elicited lethality of gastric cells, with increased risks of the recurrence and serious cardiovascular side effects. However, the detailed mechanisms underlying the reduction of DOX sensitivity remain unclear. In this study, we generated a DOX-resistant variant upon continuously treating human gastric cancer MKN45 cells with incremental concentrations of the drug, and investigated whether the gain of DOX resistance influences gene expression of four aldo-keto reductases (AKRs: 1B10, 1C1, 1C2 and 1C3). RT-PCR analysis revealed that among the enzymes AKR1B10 is most highly up-regulated during the chemoresistance induction. The up-regulation of AKR1B10 was confirmed by analyses of Western blotting and enzyme activity. The DOX sensitivity of MKN45 cells was reduced and elevated by overexpression and inhibition of AKR1B10, respectively. Compared to the parental MKN45 cells, the DOX-resistant cells had higher migrating and invasive abilities, which were significantly suppressed by addition of AKR1B10 inhibitors. Zymographic and real-time PCR analyses also revealed significant increases in secretion and expression of matrix metalloproteinase (MMP) 2 associated with DOX resistance. Moreover, the overexpression of AKR1B10 in the parental cells remarkably facilitated malignant progression (elevation of migrating and invasive potentials) and MMP2 secretion, which were lowered by the AKR1B10 inhibitors. These results suggest that AKR1B10 is a DOX-resistance gene in the gastric cancer cells, and is responsible for elevating the migrating and invasive potentials of the cells through induction of MMP2.
authors: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors: Yoshifumi
authors: Y
authors: Morikawa
authors: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors: Chihiro
authors: C
authors: Kezuka
authors: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors: Satoshi
authors: S
authors: Endo
authors: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors: Akira
authors: A
authors: Ikari
authors: Laboratory of Clinical Pharmacy, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan.
authors: Midori
authors: M
authors: Soda
authors: Laboratory of Clinical Pharmacy, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan.
authors: Keiko
authors: K
authors: Yamamura
authors: Graduate School of Science and Technology for Research, University of Toyama, Toyama 930-8555, Japan.
authors: Naoki
authors: N
authors: Toyooka
authors: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors: Ossama
authors: O
authors: El-Kabbani
authors: Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
authors: Akira
authors: A
authors: Hara
authors: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: matsunagat@gifu-pu.ac.jp.
authors: Toshiyuki
authors: T
authors: Matsunaga
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004317:Doxorubicin; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D020778:Matrix Metalloproteinase 2
keywords: Aldo–keto reductase 1B10; Chemoresistance; Doxorubicin; Gastric cancer; Malignancy; Matrix metalloproteinase