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

Wang,Dongdong; Saga,Yasushi; Sato,Naoto; Nakamura,Toshikazu; Takikawa,Osamu; Mizukami,Hiroaki; Matsubara,Shigeki; Fujiwara,Hiroyuki

doi:10.3892/ijo.2016.3486

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
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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
Published online on: April 14, 2016 https://doi.org/10.3892/ijo.2016.3486
Pages: 2303-2309
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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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1	Higuchi K and Hayaishi O: Enzymic formation of D-kynurenine from D-tryptophan. Arch Biochem Biophys. 120:397–403. 1967. View Article : Google Scholar : PubMed/NCBI
2	Yamamoto S and Hayaishi O: Tryptophan pyrrolase of rabbit intestine. D- and L-tryptophan-cleaving enzyme or enzymes. J Biol Chem. 242:5260–5266. 1967.PubMed/NCBI
3	Shimizu T, Nomiyama S, Hirata F and Hayaishi O: Indoleamine 2,3-dioxygenase. Purification and some properties. J Biol Chem. 253:4700–4706. 1978.PubMed/NCBI
4	Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T and Van den Eynde BJ: Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 9:1269–1274. 2003. View Article : Google Scholar : PubMed/NCBI
5	Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C and Mellor AL: Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 281:1191–1193. 1998. View Article : Google Scholar : PubMed/NCBI
6	Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, Moretta L, Moretta A and Vitale M: The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood. 108:4118–4125. 2006. View Article : Google Scholar : PubMed/NCBI
7	Nonaka H, Saga Y, Fujiwara H, Akimoto H, Yamada A, Kagawa S, Takei Y, Machida S, Takikawa O and Suzuki M: Indoleamine 2,3-dioxygenase promotes peritoneal dissemination of ovarian cancer through inhibition of natural killer cell function and angiogenesis promotion. Int J Oncol. 38:113–120. 2011.
8	Takikawa O, Kuroiwa T, Yamazaki F and Kido R: Mechanism of interferon-gamma action. Characterization of indoleamine 2,3-dioxygenase in cultured human cells induced by interferon-gamma and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity. J Biol Chem. 263:2041–2048. 1988.PubMed/NCBI
9	Fujigaki S, Saito K, Sekikawa K, Tone S, Takikawa O, Fujii H, Wada H, Noma A and Seishima M: Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-gamma-independent mechanism. Eur J Immunol. 31:2313–2318. 2001. View Article : Google Scholar : PubMed/NCBI
10	Matsumoto K, Date K, Shimura H and Nakamura T: Acquisition of invasive phenotype in gallbladder cancer cells via mutual interaction of stromal fibroblasts and cancer cells as mediated by hepatocyte growth factor. Jpn J Cancer Res. 87:702–710. 1996. View Article : Google Scholar : PubMed/NCBI
11	Nakamura T, Matsumoto K, Kiritoshi A, Tano Y and Nakamura T: Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: In vitro analysis of tumor-stromal interactions. Cancer Res. 57:3305–3313. 1997.PubMed/NCBI
12	Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A and Comoglio PM: Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol. 119:629–641. 1992. View Article : Google Scholar : PubMed/NCBI
13	Grant DS, Kleinman HK, Goldberg ID, Bhargava MM, Nickoloff BJ, Kinsella JL, Polverini P and Rosen EM: Scatter factor induces blood vessel formation in vivo. Proc Natl Acad Sci USA. 90:1937–1941. 1993. View Article : Google Scholar : PubMed/NCBI
14	Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K and Shimizu S: Molecular cloning and expression of human hepatocyte growth factor. Nature. 342:440–443. 1989. View Article : Google Scholar : PubMed/NCBI
15	Date K, Matsumoto K, Shimura H, Tanaka M and Nakamura T: HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. FEBS Lett. 420:1–6. 1997. View Article : Google Scholar
16	Matsumoto K and Nakamura T: Mechanisms and significance of bifunctional NK4 in cancer treatment. Biochem Biophys Res Commun. 333:316–327. 2005. View Article : Google Scholar : PubMed/NCBI
17	Kuba K, Matsumoto K, Date K, Shimura H, Tanaka M and Nakamura T: HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Res. 60:6737–6743. 2000.PubMed/NCBI
18	Saga Y, Mizukami H, Suzuki M, Urabe M, Kume A, Nakamura T, Sato I and Ozawa K: Expression of HGF/NK4 in ovarian cancer cells suppresses intraperitoneal dissemination and extends host survival. Gene Ther. 8:1450–1455. 2001. View Article : Google Scholar : PubMed/NCBI
19	Tomioka D, Maehara N, Kuba K, Mizumoto K, Tanaka M, Matsumoto K and Nakamura T: Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res. 61:7518–7524. 2001.PubMed/NCBI
20	Son G, Hirano T, Seki E, Iimuro Y, Nukiwa T, Matsumoto K, Nakamura T and Fujimoto J: Blockage of HGF/c-Met system by gene therapy (adenovirus-mediated NK4 gene) suppresses hepatocellular carcinoma in mice. J Hepatol. 45:688–695. 2006. View Article : Google Scholar : PubMed/NCBI
21	Du W, Hattori Y, Yamada T, Matsumoto K, Nakamura T, Sagawa M, Otsuki T, Niikura T, Nukiwa T and Ikeda Y: NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells: Molecular targeting of angiogenic growth factor. Blood. 109:3042–3049. 2007.
22	Kubota T, Taiyoh H, Matsumura A, Murayama Y, Ichikawa D, Okamoto K, Fujiwara H, Ikoma H, Nakanishi M, Kikuchi S, et al: Gene transfer of NK4, an angiogenesis inhibitor, induces CT26 tumor regression via tumor-specific T lymphocyte activation. Int J Cancer. 125:2879–2886. 2009. View Article : Google Scholar : PubMed/NCBI
23	Suzuki Y, Sakai K, Ueki J, Xu Q, Nakamura T, Shimada H, Nakamura T and Matsumoto K: Inhibition of Met/HGF receptor and angiogenesis by NK4 leads to suppression of tumor growth and migration in malignant pleural mesothelioma. Int J Cancer. 127:1948–1957. 2010. View Article : Google Scholar : PubMed/NCBI
24	Matsumoto G, Omi Y, Lee U, Kubota E and Tabata Y: NK4 gene therapy combined with cisplatin inhibits tumour growth and metastasis of squamous cell carcinoma. Anticancer Res. 31:105–111. 2011.PubMed/NCBI
25	Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL, Haley PJ, Burn TC, Waeltz P, Sparks RB, Yue EW, et al: Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther. 9:489–498. 2010. View Article : Google Scholar : PubMed/NCBI
26	Fogh J, Wright WC and Loveless JD: Absence of HeLa cell contamination in 169 cell lines derived from human tumors. J Natl Cancer Inst. 58:209–214. 1977.PubMed/NCBI
27	Yagita M, Huang CL, Umehara H, Matsuo Y, Tabata R, Miyake M, Konaka Y and Takatsuki K: A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation. Leukemia. 14:922–930. 2000. View Article : Google Scholar : PubMed/NCBI
28	Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L, Blake R, et al: A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 63:7345–7355. 2003.PubMed/NCBI
29	Guo M, Joiakim A and Reiners JJ Jr: Suppression of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated aryl hydrocarbon receptor transformation and CYP1A1 induction by the phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). Biochem Pharmacol. 60:635–642. 2000. View Article : Google Scholar : PubMed/NCBI
30	Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, et al: Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 273:18623–18632. 1998. View Article : Google Scholar : PubMed/NCBI
31	Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, et al: A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene. 26:2435–2444. 2007. View Article : Google Scholar
32	Saga Y, Mizukami H, Suzuki M, Kohno T, Urabe M, Ozawa K and Sato I: Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells. Clin Cancer Res. 8:1248–1252. 2002.PubMed/NCBI
33	Saga Y, Mizukami H, Takei Y, Ozawa K and Suzuki M: Suppression of cell migration in ovarian cancer cells mediated by PTEN overexpression. Int J Oncol. 23:1109–1113. 2003.PubMed/NCBI
34	Takei Y, Saga Y, Mizukami H, Takayama T, Ohwada M, Ozawa K and Suzuki M: Overexpression of PTEN in ovarian cancer cells suppresses i.p. dissemination and extends survival in mice. Mol Cancer Ther. 7:704–711. 2008. View Article : Google Scholar : PubMed/NCBI
35	Urabe M, Hasumi Y, Ogasawara Y, Matsushita T, Kamoshita N, Nomoto A, Colosi P, Kurtzman GJ, Tobita K and Ozawa K: A novel dicistronic AAV vector using a short IRES segment derived from hepatitis C virus genome. Gene. 200:157–162. 1997. View Article : Google Scholar : PubMed/NCBI
36	Wang D, Saga Y, Mizukami H, Sato N, Nonaka H, Fujiwara H, Takei Y, Machida S, Takikawa O, Ozawa K, et al: Indoleamine-2,3-dioxygenase, an immunosuppressive enzyme that inhibits natural killer cell function, as a useful target for ovarian cancer therapy. Int J Oncol. 40:929–934. 2012.
37	Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, et al: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 275:1943–1947. 1997. View Article : Google Scholar : PubMed/NCBI
38	Cantley LC and Neel BG: New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA. 96:4240–4245. 1999. View Article : Google Scholar : PubMed/NCBI
39	Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, Sorenson EC, Popow R, Ariyan C, Rossi F, et al: Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tu mor through the inhibition of Ido. Nat Med. 17:1094–1100. 2011. View Article : Google Scholar : PubMed/NCBI