Combinatorial cytotoxicity of gemcitabine and cytokine-activated killer cells in hepatocellular carcinoma via the NKG2D-MICA/B system

Takashi Morisaki, Hideya Ohnishi, Norihiro Koya, Akifumi Kiyota, Hiroto Tanaka, Masayo Umebayashi, Toshitatsu Ogino, Iori Nagamatsu, Mitsuo Katano

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Abstract

Aim: Natural-killer group 2, member D (NKG2D) is an activating receptor on natural killer cells and activated T-cells, designated cytokine-activated killer (CAK) cells here. The MHC class I chain-related A and B (MICA and MICB, respectively) are ligands of NKG2D and are expressed on various human tumor cells, including hepatocellular carcinoma (HCC) cells. Here, we investigate whether gemcitabine, a chemotherapeutic agent, affects MICA/B expression in HCC. Materials and Methods: We used ELISA, RT-PCR and adherent target detachment assays to determine expression of MICA/B in HepG2 HCC cells and the level of cellular cytotoxicity generated by treatment with gemcitabine and/or CAK cells. Results: Surface expression of MICA/B was evident after gemcitabine treatment, and MICB-specific mRNA was up-regulated. Pre-treatment with gemcitabine and subsequent exposure to CAK cells induced greater cytotoxicity than either treatment alone. Inclusion of soluble MICB significantly reduced cytotoxicity. Conclusion: Gemcitabine induced MICA/B expression in HepG2 cells, resulting in synergistic enhancement of the cytotoxic effects of NKG2D-high CAK cells. The combination of gemcitabine and CAK cells may have clinical therapeutic significance for HCC.

Original languageEnglish
Pages (from-to)2505-2510
Number of pages6
JournalAnticancer Research
Volume31
Issue number7
Publication statusPublished - Jul 2011

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gemcitabine
Hepatocellular Carcinoma
Cytokines
Cytokine-Induced Killer Cells
Natural Killer Cell Receptors
Therapeutics
Hep G2 Cells
Enzyme-Linked Immunosorbent Assay

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

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Combinatorial cytotoxicity of gemcitabine and cytokine-activated killer cells in hepatocellular carcinoma via the NKG2D-MICA/B system. / Morisaki, Takashi; Ohnishi, Hideya; Koya, Norihiro; Kiyota, Akifumi; Tanaka, Hiroto; Umebayashi, Masayo; Ogino, Toshitatsu; Nagamatsu, Iori; Katano, Mitsuo.

In: Anticancer Research, Vol. 31, No. 7, 07.2011, p. 2505-2510.

Research output: Contribution to journalArticle

Morisaki, T, Ohnishi, H, Koya, N, Kiyota, A, Tanaka, H, Umebayashi, M, Ogino, T, Nagamatsu, I & Katano, M 2011, 'Combinatorial cytotoxicity of gemcitabine and cytokine-activated killer cells in hepatocellular carcinoma via the NKG2D-MICA/B system', Anticancer Research, vol. 31, no. 7, pp. 2505-2510.
Morisaki, Takashi ; Ohnishi, Hideya ; Koya, Norihiro ; Kiyota, Akifumi ; Tanaka, Hiroto ; Umebayashi, Masayo ; Ogino, Toshitatsu ; Nagamatsu, Iori ; Katano, Mitsuo. / Combinatorial cytotoxicity of gemcitabine and cytokine-activated killer cells in hepatocellular carcinoma via the NKG2D-MICA/B system. In: Anticancer Research. 2011 ; Vol. 31, No. 7. pp. 2505-2510.
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AU - Kiyota, Akifumi

AU - Tanaka, Hiroto

AU - Umebayashi, Masayo

AU - Ogino, Toshitatsu

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AU - Katano, Mitsuo

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AB - Aim: Natural-killer group 2, member D (NKG2D) is an activating receptor on natural killer cells and activated T-cells, designated cytokine-activated killer (CAK) cells here. The MHC class I chain-related A and B (MICA and MICB, respectively) are ligands of NKG2D and are expressed on various human tumor cells, including hepatocellular carcinoma (HCC) cells. Here, we investigate whether gemcitabine, a chemotherapeutic agent, affects MICA/B expression in HCC. Materials and Methods: We used ELISA, RT-PCR and adherent target detachment assays to determine expression of MICA/B in HepG2 HCC cells and the level of cellular cytotoxicity generated by treatment with gemcitabine and/or CAK cells. Results: Surface expression of MICA/B was evident after gemcitabine treatment, and MICB-specific mRNA was up-regulated. Pre-treatment with gemcitabine and subsequent exposure to CAK cells induced greater cytotoxicity than either treatment alone. Inclusion of soluble MICB significantly reduced cytotoxicity. Conclusion: Gemcitabine induced MICA/B expression in HepG2 cells, resulting in synergistic enhancement of the cytotoxic effects of NKG2D-high CAK cells. The combination of gemcitabine and CAK cells may have clinical therapeutic significance for HCC.

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