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The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway

  • Authors:
    • Dongdong Wang
    • Yasushi Saga
    • Naoto Sato
    • Toshikazu Nakamura
    • Osamu Takikawa
    • Hiroaki Mizukami
    • Shigeki Matsubara
    • Hiroyuki Fujiwara
  • View Affiliations / Copyright

    Affiliations: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan, Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, Osaka, Japan, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan, Division of Genetic Therapeutics, Center for Molecular Medicine, School of Medicine, Jichi Medical University, Tochigi, Japan
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2303-2309
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    Published online on: April 14, 2016
       https://doi.org/10.3892/ijo.2016.3486
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Abstract

Indoleamine-2,3-dioxygenase (IDO) is an immunosuppressive enzyme involved in tumor malignancy. However, the regulatory mechanism underlying its involvement remains largely uncharacterized. The present study aimed to investigate the hypothesis that NK4, an antagonist of hepatocyte growth factor (HGF), can regulate IDO and to characterize the signaling mechanism involved. Following successful transfection of the human ovarian cancer cell line SKOV-3 (which constitutively expresses IDO) with an NK4 expression vector, we observed that NK4 expression suppressed IDO expression; furthermore, NK4 expression did not suppress cancer cell growth in vitro [in the absence of natural killer (NK) cells], but did influence tumor growth in vivo. In addition, NK4 enhanced the sensitivity of cancer cells to NK cells in vitro and promoted NK cell accumulation in the tumor stroma in vivo. In an effort to clarify the mechanisms by which NK4 interacts with IDO, we performed investigations utilizing various biochemical inhibitors. The results of these investigations were as follows. First, c-Met (a receptor of HGF) tyrosine kinase inhibitor PHA-665752, and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 both suppress IDO expression. Second, enhanced expression of PTEN (a known tumor suppressor) via negative regulation within a PI3K-AKT pathway, inhibits IDO expression. Conversely, neither the MEK1/2 inhibitor U0126 nor the STAT3 inhibitor WP1066 affects IDO expression. These results suggest that NK4 inhibits IDO expression via a c-Met-PI3K-AKT signaling pathway.
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Copy and paste a formatted citation
Spandidos Publications style
Wang D, Saga Y, Sato N, Nakamura T, Takikawa O, Mizukami H, Matsubara S and Fujiwara H: The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway. Int J Oncol 48: 2303-2309, 2016.
APA
Wang, D., Saga, Y., Sato, N., Nakamura, T., Takikawa, O., Mizukami, H. ... Fujiwara, H. (2016). The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway. International Journal of Oncology, 48, 2303-2309. https://doi.org/10.3892/ijo.2016.3486
MLA
Wang, D., Saga, Y., Sato, N., Nakamura, T., Takikawa, O., Mizukami, H., Matsubara, S., Fujiwara, H."The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway". International Journal of Oncology 48.6 (2016): 2303-2309.
Chicago
Wang, D., Saga, Y., Sato, N., Nakamura, T., Takikawa, O., Mizukami, H., Matsubara, S., Fujiwara, H."The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway". International Journal of Oncology 48, no. 6 (2016): 2303-2309. https://doi.org/10.3892/ijo.2016.3486
Copy and paste a formatted citation
x
Spandidos Publications style
Wang D, Saga Y, Sato N, Nakamura T, Takikawa O, Mizukami H, Matsubara S and Fujiwara H: The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway. Int J Oncol 48: 2303-2309, 2016.
APA
Wang, D., Saga, Y., Sato, N., Nakamura, T., Takikawa, O., Mizukami, H. ... Fujiwara, H. (2016). The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway. International Journal of Oncology, 48, 2303-2309. https://doi.org/10.3892/ijo.2016.3486
MLA
Wang, D., Saga, Y., Sato, N., Nakamura, T., Takikawa, O., Mizukami, H., Matsubara, S., Fujiwara, H."The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway". International Journal of Oncology 48.6 (2016): 2303-2309.
Chicago
Wang, D., Saga, Y., Sato, N., Nakamura, T., Takikawa, O., Mizukami, H., Matsubara, S., Fujiwara, H."The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway". International Journal of Oncology 48, no. 6 (2016): 2303-2309. https://doi.org/10.3892/ijo.2016.3486
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