Suppression of VEGF expression through interruption of the HIF‑1α and Akt signaling cascade modulates the anti‑angiogenic activity of DAPK in ovarian carcinoma cells

Park,Sung Taek; Kim,Boh-Ram; Park,Sung Ho; Lee,Jeong Heon; Lee,Eun-Ju; Lee,Seung-Hoon; Rho,Seung Bae

doi:10.3892/or.2013.2928

Suppression of VEGF expression through interruption of the HIF‑1α and Akt signaling cascade modulates the anti‑angiogenic activity of DAPK in ovarian carcinoma cells

Authors:
- Sung Taek Park
- Boh-Ram Kim
- Sung Ho Park
- Jeong Heon Lee
- Eun-Ju Lee
- Seung-Hoon Lee
- Seung Bae Rho
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Affiliations: Department of Obstetrics and Gynecology, Hallym University, Seoul 150‑950, Republic of Korea, Research Institute, National Cancer Center, Goyang-si, Gyeonggi‑do 410‑769, Republic of Korea, Department of Obstetrics and Gynecology, Chonbuk National University Medical School, Jeonju 561‑712, Republic of Korea, Department of Obstetrics and Gynecology, Chung‑Ang University School of Medicine/Chung‑Ang University Hospital, Seoul 156-755, Republic of Korea, Department of Life Science, Yong In University, Yongin-si, Gyeonggi-do 449-714, Republic of Korea
Published online on: December 16, 2013 https://doi.org/10.3892/or.2013.2928
Pages: 1021-1029

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Abstract

Death-associated protein kinase (DAPK) plays an important role in apoptosis regulation and has been shown to maintain antitumor and metastasis suppressor properties. In the present study, we investigated whether DAPK overexpression may mediate vascular endothelial growth factor (VEGF)/hypoxia-inducible factor-1α (HIF-1α) expression and angiogenic activity in the human carcinoma cell model system. VEGF plays a pivotal role in tumor angiogenesis and tumorigenesis. We found that DAPK significantly downregulated VEGF-induced endothelial cell proliferation, migration and tube formation as well as VEGF receptor-2 (VEGFR-2) phosphorylation in vitro. In addition, DAPK exhibited potent anti-angiogenic activity and clearly decreased the levels of VEGF and HIF-1α expression, a key regulator for angiogenesis. Notably, our results strongly indicated that DAPK can disturb VEGFR-2 transcriptional activity by inhibiting VEGFR-2 phosphorylation through the PI3K/Akt signaling cascade. Collectively, our study identified a novel function of DAPK in regulating cellular VEGF/HIF-1α activity during tumorigenesis, which may act together with its anti-angiogenic function to inhibit tumor progression.

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1	Cohen O, Inbal B, Kissil JL, et al: DAP-kinase participates in TNF-α- and Fas-induced apoptosis and its function requires the death domain. J Cell Biol. 146:141–148. 1999.
2	Jang CW, Chen CH, Chen CC, et al: TGF-β induces apoptosis through Smad-mediated expression of DAP-kinase. Nat Cell Biol. 4:51–58. 2002.
3	Bialik S and Kimchi A: The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem. 75:189–210. 2006. View Article : Google Scholar : PubMed/NCBI
4	Deiss LP, Feinstein E, Berissi H, Cohen O and Kimchi A: Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev. 9:15–30. 1995. View Article : Google Scholar : PubMed/NCBI
5	Cohen O, Feinstein E and Kimchi A: DAP-kinase is a Ca²⁺/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity. EMBO J. 16:998–1008. 1997.
6	Raveh T, Droguett G, Horwitz MS, DePinho RA and Kimchi A: DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat Cell Biol. 3:1–7. 2001.PubMed/NCBI
7	Michie AM, McCaig AM, Nakagawa R and Vukovic M: Death-associated protein kinase (DAPK) and signal transduction: regulation in cancer. FEBS J. 277:74–80. 2010. View Article : Google Scholar : PubMed/NCBI
8	Sanchez-Cespedes M, Esteller M, Wu L, et al: Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res. 60:892–895. 2000.PubMed/NCBI
9	Kim DH, Nelson HH, Wiencke JK, et al: Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer. Oncogene. 20:1765–1770. 2001. View Article : Google Scholar : PubMed/NCBI
10	Dansranjavin T, Möbius C, Tannapfel A, et al: E-cadherin and DAP kinase in pancreatic adenocarcinoma and corresponding lymph node metastases. Oncol Rep. 15:1125–1131. 2006.PubMed/NCBI
11	Kissil JL, Feinstein E, Cohen O, et al: DAP-kinase loss of expression in various carcinoma and B-cell lymphoma cell lines: possible implications for role as tumor suppressor gene. Oncogene. 15:403–407. 1997. View Article : Google Scholar : PubMed/NCBI
12	Katzenellenbogen RA, Baylin SB and Herman JG: Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood. 93:4347–4353. 1999.PubMed/NCBI
13	Henshall DC, Araki T, Schindler CK, et al: Expression of death-associated protein kinase and recruitment to the tumor necrosis factor signaling pathway following brief seizures. J Neurochem. 86:1260–1270. 2003. View Article : Google Scholar : PubMed/NCBI
14	Anjum R, Roux PP, Ballif BA, Gygi SP and Blenis J: The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling. Curr Biol. 15:1762–1767. 2005. View Article : Google Scholar : PubMed/NCBI
15	Chen CH, Wang WJ, Kuo JC, et al: Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. EMBO J. 24:294–304. 2005. View Article : Google Scholar : PubMed/NCBI
16	Liambi F, Lourenço FC, Gozuacik D, et al: The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase. EMBO J. 24:1192–1201. 2005. View Article : Google Scholar : PubMed/NCBI
17	Tang X, Khuri FR, Lee JJ, et al: Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non-small-cell lung cancer. J Natl Cancer Inst. 92:1511–1516. 2000. View Article : Google Scholar : PubMed/NCBI
18	Harden SV, Tokumaru Y, Westra WH, et al: Gene promoter hypermethylation in tumors and lymph nodes of stage I lung cancer patients. Clin Cancer Res. 9:1370–1375. 2003.PubMed/NCBI
19	Lu C, Soria JC, Tang X, et al: Prognostic factors in resected stage I non-small-cell lung cancer: A multivariate analysis of six molecular markers. J Clin Oncol. 22:4575–4583. 2004. View Article : Google Scholar : PubMed/NCBI
20	Risau W: Mechanisms of angiogenesis. Nature. 386:671–674. 1997. View Article : Google Scholar : PubMed/NCBI
21	Denny WA: Prodrug strategies in cancer therapy. Eur J Med Chem. 36:577–595. 2001. View Article : Google Scholar : PubMed/NCBI
22	Blagosklonny MV: Antiangiogenic therapy and tumor progression. Cancer Cell. 5:13–17. 2004. View Article : Google Scholar
23	Olson TA, Mohanraj D, Carson LF and Ramakrishnan S: Vascular permeability factor gene expression in normal and neoplastic human ovaries. Cancer Res. 54:276–280. 1994.PubMed/NCBI
24	Paley PJ, Staskus KA, Gebhard K, et al: Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer. 80:98–106. 1997. View Article : Google Scholar : PubMed/NCBI
25	Ohta Y, Tomita Y, Oda M, et al: Tumor angiogenesis and recurrence in stage I non-small cell lung cancer. Ann Thorac Surg. 68:1034–1038. 1999. View Article : Google Scholar : PubMed/NCBI
26	Ishigami SI, Arii S, Furutani M, et al: Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer. 78:1379–1384. 1998. View Article : Google Scholar : PubMed/NCBI
27	Yamamoto S, Konishi I, Mandai M, et al: Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer. 76:1221–1227. 1997. View Article : Google Scholar : PubMed/NCBI
28	Spannuth WA, Nick AM, Jennings NB, et al: Functional significance of VEGFR-2 on ovarian cancer cells. Int J Cancer. 124:1045–1053. 2009. View Article : Google Scholar : PubMed/NCBI
29	Lee OH, Kim YM, Lee YM, et al: Sphingosine 1-phosphate induces angiogenesis: its angiogenic action and signaling mechanism in human umbilical vein endothelial cells. Biochem Biophys Res Commun. 264:743–750. 1999. View Article : Google Scholar : PubMed/NCBI
30	Byun HJ, Lee JH, Kim BR, et al: Anti-angiogenic effects of thioridazine involving the FAK-mTOR pathway. Microvasc Res. 84:227–234. 2012. View Article : Google Scholar : PubMed/NCBI
31	Senger DR, Ledbetter SR, Claffey KP, et al: Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin. Am J Pathol. 149:293–305. 1996.
32	Benelli R and Albini A: In vitro models of angiogenesis: the use of Matrigel. Int J Biol Markers. 14:243–246. 1999.PubMed/NCBI
33	Fruman DA, Mauvais-Jarvis F, Pollard DA, et al: Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α. Nat Genet. 26:379–382. 2000.PubMed/NCBI
34	Lee KB, Byun HJ, Park SH, et al: CYR61 controls p53 and NF-κB expression through PI3K/Akt/mTOR pathways in carboplatin-induced ovarian cancer cells. Cancer Lett. 315:86–95. 2012.PubMed/NCBI
35	Rho SB, Kim MJ, Lee JS, et al: Genetic dissection of protein-protein interactions in multi-tRNA synthetase complex. Proc Natl Acad Sci USA. 96:4488–4493. 1999. View Article : Google Scholar : PubMed/NCBI
36	Rho SB, Song YJ, Lim MC, et al: Programmed cell death 6 (PDCD6) inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of VEGFR-2. Cell Signal. 24:131–139. 2012. View Article : Google Scholar : PubMed/NCBI
37	Plate KH: Control of tumor growth via inhibition of tumor angiogenesis. Adv Exp Med Biol. 451:57–61. 1998. View Article : Google Scholar : PubMed/NCBI
38	Ferrara N: Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol. 29(Suppl 16): S10–S14. 2002. View Article : Google Scholar : PubMed/NCBI
39	Mu J, Abe Y, Tsutsui T, et al: Inhibition of growth and metastasis of ovarian carcinoma by administering a drug capable of interfering with vascular endothelial growth factor activity. Jpn J Cancer Res. 87:963–971. 1996. View Article : Google Scholar : PubMed/NCBI
40	Hartenbach EM, Olson TA, Goswitz JJ, et al: Vascular endothelial growth factor (VEGF) expression and survival in human epithelial ovarian carcinomas. Cancer Lett. 121:169–175. 1997. View Article : Google Scholar : PubMed/NCBI
41	Ferrara N and Davis-Smyth T: The biology of vascular endothelial growth factor. Endocr Rev. 18:4–25. 1997. View Article : Google Scholar
42	Gerber HP, Kowalski J, Sherman D, Eberhard DA and Ferrara N: Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularisation requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res. 60:6253–6258. 2000.
43	Semenza GL: Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol. 35:71–103. 2000. View Article : Google Scholar : PubMed/NCBI
44	Zhong H, De Marzo AM, Laughner E, et al: Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res. 59:5830–5835. 1999.
45	Maxwell PH, Dachs GU, Gleadle JM, et al: Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA. 94:8104–8109. 1997. View Article : Google Scholar : PubMed/NCBI
46	Forsythe JA, Jiang BH, Iyer NV, et al: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16:4604–4613. 1996.PubMed/NCBI
47	Fang J, Xia C, Cao Z, et al: Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 19:342–353. 2005. View Article : Google Scholar : PubMed/NCBI
48	Altomare DA, Wang HQ, Skele KL, et al: AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 23:5853–5857. 2004. View Article : Google Scholar : PubMed/NCBI
49	Olsson AK, Dimberg A, Kreuger J and Caesson-Welsh L: VEGF receptor signaling - in control of vascular function. Nat Rev Mol Cell Biol. 7:359–371. 2006. View Article : Google Scholar : PubMed/NCBI
50	Engelman JA: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 9:550–562. 2009. View Article : Google Scholar : PubMed/NCBI
51	Hanrahan AJ, Schultz N, Westfal ML, et al: Genomic complexity and AKT dependence in serous ovarian cancer. Cancer Discov. 2:56–67. 2012. View Article : Google Scholar : PubMed/NCBI
52	Guertin DA and Sabatini DM: An expanding role for mTOR in cancer. Trends Mol Med. 11:353–361. 2005. View Article : Google Scholar : PubMed/NCBI
53	Xia C, Meng Q, Cao Z, Shi X and Jiang BH: Regulation of angiogenesis and tumor growth by p110 alpha and AKT1 via VEGF expression. J Cell Physiol. 209:56–66. 2006. View Article : Google Scholar : PubMed/NCBI
54	Liby TA, Spyropoulos P, Buff Lindner H, et al: Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells. Int J Cancer. 130:532–543. 2012. View Article : Google Scholar : PubMed/NCBI