Acquisition of doxorubicin resistance facilitates migrating and invasive potentials of gastric cancer MKN45 cells through up-regulating aldo-keto reductase 1B10

Yoshifumi Morikawa, Chihiro Kezuka, Satoshi Endo, Akira Ikari, Midori Soda, Keiko Yamamura, Naoki Toyooka, Ossama El-Kabbani, Akira Hara, Toshiyuki Matsunaga

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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.
Original languageEnglish
Pages (from-to)30-39
Number of pages10
JournalChemico-Biological Interactions
Volume230
DOIs
Publication statusPublished - 2015

Keywords

  • Aldoketo reductase 1B10
  • Chemoresistance
  • Doxorubicin
  • Gastric cancer
  • Malignancy
  • Matrix metalloproteinase

Cite this

Morikawa, Yoshifumi ; Kezuka, Chihiro ; Endo, Satoshi ; Ikari, Akira ; Soda, Midori ; Yamamura, Keiko ; Toyooka, Naoki ; El-Kabbani, Ossama ; Hara, Akira ; Matsunaga, Toshiyuki. / Acquisition of doxorubicin resistance facilitates migrating and invasive potentials of gastric cancer MKN45 cells through up-regulating aldo-keto reductase 1B10. In: Chemico-Biological Interactions. 2015 ; Vol. 230. pp. 30-39.
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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.",
keywords = "Aldoketo reductase 1B10, Chemoresistance, Doxorubicin, Gastric cancer, Malignancy, Matrix metalloproteinase",
author = "Yoshifumi Morikawa and Chihiro Kezuka and Satoshi Endo and Akira Ikari and Midori Soda and Keiko Yamamura and Naoki Toyooka and Ossama El-Kabbani and Akira Hara and Toshiyuki Matsunaga",
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Acquisition of doxorubicin resistance facilitates migrating and invasive potentials of gastric cancer MKN45 cells through up-regulating aldo-keto reductase 1B10. / Morikawa, Yoshifumi; Kezuka, Chihiro; Endo, Satoshi; Ikari, Akira; Soda, Midori; Yamamura, Keiko; Toyooka, Naoki; El-Kabbani, Ossama; Hara, Akira; Matsunaga, Toshiyuki.

In: Chemico-Biological Interactions, Vol. 230, 2015, p. 30-39.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Acquisition of doxorubicin resistance facilitates migrating and invasive potentials of gastric cancer MKN45 cells through up-regulating aldo-keto reductase 1B10

AU - Morikawa, Yoshifumi

AU - Kezuka, Chihiro

AU - Endo, Satoshi

AU - Ikari, Akira

AU - Soda, Midori

AU - Yamamura, Keiko

AU - Toyooka, Naoki

AU - El-Kabbani, Ossama

AU - Hara, Akira

AU - Matsunaga, Toshiyuki

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Aldoketo reductase 1B10

KW - Chemoresistance

KW - Doxorubicin

KW - Gastric cancer

KW - Malignancy

KW - Matrix metalloproteinase

UR - http://goo.gl/5EnwSR

U2 - 10.1016/j.cbi.2015.02.005

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