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Article

Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification

  • Authors:
    • Hideo Tomioka
    • Toru Mukohara
    • Yu Kataoka
    • Roudy Chiminch Ekyalongo
    • Yohei  Funakoshi
    • Yasuo Imai
    • Naomi Kiyota
    • Yutaka Fujiwara
    • Hironobu Minami
  • View Affiliations / Copyright

    Affiliations: Department of Internal Medicine, Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, Department of Pathology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Saitama 343-8555, Japan
  • Pages: 551-558
    |
    Published online on: May 17, 2012
       https://doi.org/10.3892/ijo.2012.1485
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Abstract

The purpose of this study was to explore the effect of trastuzumab in enhancing the activity of chemotherapeutic agents and the molecular basis of this effect. Two gastric cancer cell types with HER2 amplification, one sensitive (NCI‑N87) and one insensitive (MKN-7) to trastuzumab, were tested for the effects of trastuzumab on cell growth and cell signaling using MTS assay and western blotting, respectively. Interaction between trastuzumab and chemotherapeutic agents (fluorouracil, doxorubicin, cisplatin and paclitaxel) was evaluated by the combination index (CI). Fluorouracil-induced apoptosis was evaluated using western blot for poly (ADP-ribose) polymerase (PARP). Trastuzumab decreased phosphorylation of S6K, showed synergistic effect with fluorouracil or doxorubicin, and increased fluorouracil-induced apoptosis in NCI-N87 cells, but not in MKN-7 cells. While the mTOR inhibitor everolimus enhanced fluorouracil-induced apoptosis in both HER2-amplified cell lines, this was not the case in the gastric cancer cell lines without HER2 amplification. Consistently, while the EGFR/HER2 inhibitor Cl-387,785 inhibited cell growth of MKN-7, this growth inhibition did not accompany decrease in phosphorylation of S6K, and the compound did not enhance fluorouracil-induced apoptosis. In summary, inhibition of the mTOR/S6K signal may be a key molecular event in enhancing fluorouracil-induced apoptosis specifically in gastric cancer cells with HER2 amplification. mTOR inhibitors may therefore be attractive alternative drugs in gastric cancers with HER2 amplification regardless of their sensitivity to trastuzumab.
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Copy and paste a formatted citation
Spandidos Publications style
Tomioka H, Mukohara T, Kataoka Y, Ekyalongo RC, Funakoshi Y, Imai Y, Kiyota N, Fujiwara Y and Minami H: Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification. Int J Oncol 41: 551-558, 2012.
APA
Tomioka, H., Mukohara, T., Kataoka, Y., Ekyalongo, R.C., Funakoshi, Y., Imai, Y. ... Minami, H. (2012). Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification. International Journal of Oncology, 41, 551-558. https://doi.org/10.3892/ijo.2012.1485
MLA
Tomioka, H., Mukohara, T., Kataoka, Y., Ekyalongo, R. C., Funakoshi, Y., Imai, Y., Kiyota, N., Fujiwara, Y., Minami, H."Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification". International Journal of Oncology 41.2 (2012): 551-558.
Chicago
Tomioka, H., Mukohara, T., Kataoka, Y., Ekyalongo, R. C., Funakoshi, Y., Imai, Y., Kiyota, N., Fujiwara, Y., Minami, H."Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification". International Journal of Oncology 41, no. 2 (2012): 551-558. https://doi.org/10.3892/ijo.2012.1485
Copy and paste a formatted citation
x
Spandidos Publications style
Tomioka H, Mukohara T, Kataoka Y, Ekyalongo RC, Funakoshi Y, Imai Y, Kiyota N, Fujiwara Y and Minami H: Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification. Int J Oncol 41: 551-558, 2012.
APA
Tomioka, H., Mukohara, T., Kataoka, Y., Ekyalongo, R.C., Funakoshi, Y., Imai, Y. ... Minami, H. (2012). Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification. International Journal of Oncology, 41, 551-558. https://doi.org/10.3892/ijo.2012.1485
MLA
Tomioka, H., Mukohara, T., Kataoka, Y., Ekyalongo, R. C., Funakoshi, Y., Imai, Y., Kiyota, N., Fujiwara, Y., Minami, H."Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification". International Journal of Oncology 41.2 (2012): 551-558.
Chicago
Tomioka, H., Mukohara, T., Kataoka, Y., Ekyalongo, R. C., Funakoshi, Y., Imai, Y., Kiyota, N., Fujiwara, Y., Minami, H."Inhibition of the mTOR/S6K signal is necessary to enhance fluorouracil-induced apoptosis in gastric cancer cells with HER2 amplification". International Journal of Oncology 41, no. 2 (2012): 551-558. https://doi.org/10.3892/ijo.2012.1485
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