Oligomer procyanidins (F2) isolated from grape seeds inhibits tumor angiogenesis and cell invasion by targeting HIF-1α in vitro

Zheng,Hong Li; Yang,Jingyu; Hou,Yue; Sun,Baoshan; Zhang,Qingchun; Mou,Yanhua; Wand,Lihui; Wu,Chunfu

doi:10.3892/ijo.2014.2744

Oligomer procyanidins (F2) isolated from grape seeds inhibits tumor angiogenesis and cell invasion by targeting HIF-1α in vitro

Authors:
- Hong Li Zheng
- Jingyu Yang
- Yue Hou
- Baoshan Sun
- Qingchun Zhang
- Yanhua Mou
- Lihui Wand
- Chunfu Wu
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Affiliations: Department of Pharmacology, Shenyang Pharmaceutical University, Shenhe District, 110016 Shenyang, P.R. China, Department of Drug Analysis, Shenyang Pharmaceutical University, Shenhe District, 110016 Shenyang, P.R. China
Published online on: November 10, 2014 https://doi.org/10.3892/ijo.2014.2744
Pages: 708-720

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Abstract

Overexpression of hypoxia-inducible factor-1 (HIF-1) α, a transcription factor which immortalizes tumors by inducing expression of the genes involved in cell survival, migration and angiogenesis, is closely associated with poor prognosis, increased risk of metastasis and increased mortality. Oligomer procyanidins (F2), a natural fraction from grape seeds, has been demonstrated to have antioxidant and antitumor activities, however the antitumor effect of F2 targeting HIF-1α remains unknown. The present study showed that F2 markedly decreased HIF-1α and the expression of its target genes in cancer cells through inactivating the EGFR-PI3K-AKT-mTOR and MAPK-ERK1/2 pathways. Moreover, F2 suppressed vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2 expressions, followed by the inhibition of tumor angiogenesis and cell invasion in a HIF-1α-dependent manner. Collectively, these findings indicate that the antitumor effect of F2 is, at least in part, mediated by suppressing HIF-1α-dependent pathway, and suggest that F2 may be a potentially useful agent for treatment of human cancer.

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1	Melillo G: Targeting hypoxia cell signaling for tumor therapy. Cancer Metastasis Rev. 26:341–352. 2007. View Article : Google Scholar : PubMed/NCBI
2	Semenza GL: HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med. 8:62–67. 2002. View Article : Google Scholar
3	Semenza GL: Targeting HIF-1 for tumor therapy. Nat Rev Cancer. 3:1–11. 2003. View Article : Google Scholar
4	Semenza GL: HIF-1: upstream and downstream of tumor metabolism. Curr Opin Genet Dev. 20:51–56. 2010. View Article : Google Scholar
5	Sun BS, Belchior GP, Ricardo da Silva JM and Spranger MI: Isolation and purification of dimeric and trimeric procyanidins from grape seeds. J Chromatogr A. 841:115–121. 1999. View Article : Google Scholar
6	Sun BS, Leandro C, Ricardo da Silva JM and Spranger MI: Separation of grape and wine proanthocyanidins according to their degree of polymerization. J Agr Food Chem. 46:1390–1396. 1998. View Article : Google Scholar
7	Spranger MI, Sun BS, Mateus A, et al: Chemical characterization and antioxidant activities of oligomeric and polymeric procyanidin fractions from grape seeds. Food Chem. 108:519–532. 2008. View Article : Google Scholar
8	Huang M, Sun BS, Zhao YQ, et al: Effects of catechin and its polymers on ethanol-induced ascorbic acid and hydroxyl radical release in mouse striatum. J Chin Nat Med. 1:34–40. 2003.
9	Zhang FJ, Yang JY, Mou YH, et al: Inhibition of U-87 human glioblastoma cell proliferation and formyl peptide receptor function by oligomer procyanidins (F2) isolated from grape seeds. Chem Biol Interact. 179:419–429. 2009. View Article : Google Scholar : PubMed/NCBI
10	Yang JY, Wang Q, Zhao RJ, et al: Identification of oligomer proanthocyanidins (F2) isolated from grape seeds as a formyl peptide receptor 1 partial agonist. Int Immunopharmacol. 15:756–763. 2013. View Article : Google Scholar : PubMed/NCBI
11	Huang J, Chen K, Chen J, et al: The G-protein-coupled formyl-peptide receptor FPR confers a more invasive phenotype on human glioblastoma cells. Br J Cancer. 102:1052–1060. 2010. View Article : Google Scholar : PubMed/NCBI
12	Liu Y, Huang J, Zhou Y, et al: The role of chemo-attractant receptors in the progression of glioma. INTECH. 21:286–305. 2011.
13	Guo L, Wang LH, Sun BS, et al: Direct in vivo evidence of protective effects of grape seed procyanidin fractions and other antioxidants against ethanol-induced oxidative DNA damage in mouse brain cells. Food Chem. 55:5881–5891. 2007. View Article : Google Scholar
14	Liu Y, Li YM, Tian RF, et al: The expression and significance of HIF-1α and GLUT-3 in glioma. Brain Res. 1304:149–154. 2009. View Article : Google Scholar : PubMed/NCBI
15	Zhang HF, Qian DZ, Tan YS, et al: Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proc Natl Acad Sci USA. 105:19579–19586. 2008. View Article : Google Scholar
16	Rapisarda A, Uranchimeg B, Scudiero DA, et al: Identification of small molecule inhibitors of hypoxia-inducible factor-1 transcriptional activation pathway. Cancer Res. 62:4316–4324. 2002.PubMed/NCBI
17	Xia MH, Bi K, Huang RL, et al: Identification of small molecule compounds that inhibit the HIF-1 signaling pathway. Mol Cancer. 8:1–13. 2009. View Article : Google Scholar
18	Chau NM, Rogers P, Aherne W, et al: Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1α induction in response to hypoxic stress and growth factors. Cancer Res. 65:4918–4928. 2005. View Article : Google Scholar : PubMed/NCBI
19	Zhao Y, Wu JH, Wu SP, et al: A recombinant cell-permeable p53 fusion protein is selectively stabilized under hypoxia and inhibits tumor cell growth. Cancer Lett. 279:101–107. 2009. View Article : Google Scholar
20	Kamat CD, Green DE, Warnke L, et al: Mutant p53 facilitates pro-angiogenic, hyper-proliferative phenotype in response to chronic relative hypoxia. Cancer Lett. 249:209–219. 2007. View Article : Google Scholar
21	Zeng M, Xiao F, Zhong X, et al: Reactive oxygen species play a central role in hexavalent chromium-induced apoptosis in Hep3B cells without the functional roles of p53 and caspase-3. Cell Physiol Biochem. 32:279–290. 2013. View Article : Google Scholar : PubMed/NCBI
22	Kizaka-Kondoh S, Kuchimaru T and Kadonosono T: Pathophysiological response to hypoxia-from the molecular mechanisms of malady to drug discovery: hypoxia-inducible factor-1 (HIF-1) active cells as a target for tumor therapy. J Pharmacol Sci. 115:440–445. 2011. View Article : Google Scholar
23	Jung HJ, Park JW, Lee JS, et al: Silibinin inhibits expression of HIF-1α through suppression of protein translation in prostate tumor cells. Biochem Biophys Res Commun. 390:71–76. 2009. View Article : Google Scholar : PubMed/NCBI
24	Jung HJ, Suh SI, Suh MH, et al: Pentamidine reduces expression of hypoxia-inducible factor-1α in DU145 and MDA-MB-231 tumor cells. Cancer Lett. 303:39–46. 2011. View Article : Google Scholar : PubMed/NCBI
25	Karar J and Maity A: PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 4:1–8. 2011. View Article : Google Scholar
26	Zhong H, Chiles K, Feldser D, et al: Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 00:1541–1545. 2000.
27	Ban HS, Uno M and Nakamura H: Suppression of hypoxia-induced HIF-1α accumulation by VEGFR inhibitors: different profiles of AAL993 versus SU5416 and KRN633. Cancer Lett. 296:17–26. 2010. View Article : Google Scholar : PubMed/NCBI
28	Zhang QZ, Tang XD, Lu QY, et al: Green tea extract and (−)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1α protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells. Mol Cancer Ther. 5:1227–1238. 2010. View Article : Google Scholar
29	Medici D and Olsen BR: Rapamycin inhibits proliferation of hemangioma endothelial cells by reducing HIF-1-dependent expression of VEGF. PLoS One. 7:e429132012. View Article : Google Scholar : PubMed/NCBI
30	Namiki A, Brogi E, Kearney M, et al: Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chem. 270:31189–31195. 2010.
31	Fujiwara S, Nakagawa K, Harada H, et al: Silencing hypoxia-inducible factor-1 inhibits cell migration and invasion under hypoxic environment in malignant gliomas. Int J Oncol. 30:793–802. 2010.
32	Lu JM, Zhang KQ, Chen S and Wen W: Grape seed extract inhibits VEGF expression via reducing HIF-1α protein expression. Carcinogenesis. 30:636–644. 2009. View Article : Google Scholar : PubMed/NCBI
33	Manolescu B, Oprea E, Busu C and Cercasov C: Natural compounds and the hypoxia-inducible factor (HIF) signaling pathway. Biochimie. 91:1347–1358. 2009. View Article : Google Scholar : PubMed/NCBI
34	Wullschleger S, Loewith R and Hall MN: TOR signaling in growth and metabolism. Cell. 124:471–484. 2006. View Article : Google Scholar : PubMed/NCBI
35	Swinson DE and O’Byrne KJ: Interactions between hypoxia and epidermal growth factor receptor in non-small-cell lung tumor. Clin Lung Cancer. 7:250–256. 2006. View Article : Google Scholar : PubMed/NCBI
36	Lu HQ, Liang K, Lu Y and Fan Z: The anti-EGFR antibody cetuximab sensitizes human head and neck squamous cell carcinoma cells to radiation in part through inhibiting radiation-induced upregulation of HIF-1α. Cancer Lett. 322:78–85. 2012. View Article : Google Scholar : PubMed/NCBI
37	Cheung W, Wellman TL and Lounsbury KM: VEGF and HIF-1α expression are increased in advanced stages of epithelial ovarian tumor. Gynecol Oncol. 91:513–517. 2003. View Article : Google Scholar
38	Ahn JK, Koh EM, Cha HS, et al: Role of hypoxia-inducible factor-1 in hypoxia-induced expressions of IL-8, MMP-1 and MMP-3 in rheumatoid fibroblast like. Rheumatology. 47:834–839. 2003. View Article : Google Scholar
39	Wang XB, Li CX, Chen Y, et al: Hypoxia enhances CXCR4 expression favoring microglia migration via HIF-1α activation. Biochem Biophys Res Commun. 371:283–288. 2008. View Article : Google Scholar : PubMed/NCBI
40	Berchner Pfannschmidt U, Frede S, Wotzlaw C and Fandrey J: Imaging of the hypoxia-inducible factor pathway: insights into oxygen sensing. Eur Respir J. 32:210–217. 2008. View Article : Google Scholar : PubMed/NCBI
41	Semenza GL: Hypoxia-inducible factors in physiology and medicine. Cell. 148:399–408. 2012. View Article : Google Scholar : PubMed/NCBI
42	Wolff M, Jelkmann W, Dunst J and Depping R: The aryl hydrocarbon receptor nuclear translocator (ARNT/HIF-1β) is influenced by hypoxia and hypoxia-mimetics. Cell Physiol Biochem. 32:849–858. 2013. View Article : Google Scholar