title: The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway.
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.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saga
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Sato
authors.affiliation: Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, Osaka, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takikawa
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsubara
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D002070:Butadienes; D002867:Chromones; C066855:HGF protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles; D009025:Morpholines; D009570:Nitriles; D011725:Pyridines; D013450:Sulfones; D020032:Tyrphostins; C113580:U 0126; C519885:WP1066; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human