Targeting glutamine metabolism and the focal adhesion kinase additively inhibits the mammalian target of the rapamycin pathway in spheroid cancer stem-like properties of ovarian clear cell carcinoma in vitro

  • Authors:
    • Masakazu Sato
    • Kei Kawana
    • Katsuyuki Adachi
    • Asaha Fujimoto
    • Mitsuyo Yoshida
    • Hiroe Nakamura
    • Haruka Nishida
    • Tomoko Inoue
    • Ayumi Taguchi
    • Juri Ogishima
    • Satoko Eguchi
    • Aki Yamashita
    • Kensuke Tomio
    • Osamu Wada-Hiraike
    • Katsutoshi Oda
    • Takeshi Nagamatsu
    • Yutaka Osuga
    • Tomoyuki Fujii
  • View Affiliations

  • Published online on: February 23, 2017     https://doi.org/10.3892/ijo.2017.3891
  • Pages: 1431-1438
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Abstract

Ovarian cancer is one of the leading causes of death in the world, which is linked to its resistance to chemotherapy. Strategies to overcome chemoresistance have been keenly investigated. Culturing cancer cells in suspension, which results in formation of spheroids, is a more accurate reflection of clinical cancer behavior in vitro than conventional adherent cultures. By performing RNA-seq analysis, we found that the focal adhesion pathway was essential in spheroids. The phosphorylation of focal adhesion kinase (FAK) was increased in spheroids compared to adherent cells, and inhibition of FAK in spheroids resulted in inhibition of the downstream mammalian target of the rapamycin (mTOR) pathway in ovarian clear cell carcinomas. This result also suggested that only using a FAK inhibitor might have limitations because the phosphorylation level of FAK could not be reduced to the level in adherent cells, and it appeared that some combination therapies might be necessary. We previously reported that glutamine and glutamate concentrations were higher in spheroids than adherent cells, and we investigated a synergistic effect targeting glutamine metabolism with FAK inhibition on the mTOR pathway. The combination of AOA, a pan-transaminase inhibitor, and PF 573228, a FAK inhibitor, additively inhibited the mTOR pathway in spheroids from ovarian clear cell carcinomas. Our in vitro study proposed a rationale for the positive and negative effects of using FAK inhibitors in ovarian clear cell carcinomas and suggested that targeting glutamine metabolism could overcome the limitation of FAK inhibitors by additively inhibiting the mTOR pathway.
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April-2017
Volume 50 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Sato M, Kawana K, Adachi K, Fujimoto A, Yoshida M, Nakamura H, Nishida H, Inoue T, Taguchi A, Ogishima J, Ogishima J, et al: Targeting glutamine metabolism and the focal adhesion kinase additively inhibits the mammalian target of the rapamycin pathway in spheroid cancer stem-like properties of ovarian clear cell carcinoma in vitro. Int J Oncol 50: 1431-1438, 2017
APA
Sato, M., Kawana, K., Adachi, K., Fujimoto, A., Yoshida, M., Nakamura, H. ... Fujii, T. (2017). Targeting glutamine metabolism and the focal adhesion kinase additively inhibits the mammalian target of the rapamycin pathway in spheroid cancer stem-like properties of ovarian clear cell carcinoma in vitro. International Journal of Oncology, 50, 1431-1438. https://doi.org/10.3892/ijo.2017.3891
MLA
Sato, M., Kawana, K., Adachi, K., Fujimoto, A., Yoshida, M., Nakamura, H., Nishida, H., Inoue, T., Taguchi, A., Ogishima, J., Eguchi, S., Yamashita, A., Tomio, K., Wada-Hiraike, O., Oda, K., Nagamatsu, T., Osuga, Y., Fujii, T."Targeting glutamine metabolism and the focal adhesion kinase additively inhibits the mammalian target of the rapamycin pathway in spheroid cancer stem-like properties of ovarian clear cell carcinoma in vitro". International Journal of Oncology 50.4 (2017): 1431-1438.
Chicago
Sato, M., Kawana, K., Adachi, K., Fujimoto, A., Yoshida, M., Nakamura, H., Nishida, H., Inoue, T., Taguchi, A., Ogishima, J., Eguchi, S., Yamashita, A., Tomio, K., Wada-Hiraike, O., Oda, K., Nagamatsu, T., Osuga, Y., Fujii, T."Targeting glutamine metabolism and the focal adhesion kinase additively inhibits the mammalian target of the rapamycin pathway in spheroid cancer stem-like properties of ovarian clear cell carcinoma in vitro". International Journal of Oncology 50, no. 4 (2017): 1431-1438. https://doi.org/10.3892/ijo.2017.3891