Naringenin modulates the metastasis of human prostate cancer cells by down regulating the matrix metalloproteinases -2/-9 via ROS/ERK1/2 pathways
Metastasis is a multifactorial condition that complicates cancer treatment options and widens the target of treatment. Matrix mettalopriteinases (MMPs) of the extracellular matrix (ECM) are involved in metastasis, thus they present as potential targets in halting cancer metastasis. The study was undertaken to investigate the influence of naringenin, a naturally occurring flavonoid on the metastasis of human prostate cancer cells (PC-3 and DU145). Naringenin was observed to be effective in reducing the viability and migratory percentage of PC-3 and DU145 cells. Naringenin significantly reduced the expression and activities of the chief MMPs (MMP-2 and MMP-9) as assessed by western blotting, real-time PCR and gelatin zymography analysis. The influence of naringenin on extracellular signal-regulated kinase (ERK) -ERK1/2 was analysed by western blotting. The results indicated that naringenin was able to effectively inhibit ERK1/2. Naringenin exposure also significantly suppressed the levels of reactive oxygen species (ROS). Naringenin thus stands as an effective chemotherapeutic agent for prostate cancer treatment that could be further explored.
Aimes RT, Quigley JP. Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4- and 1/4-length fragments. J Biol Chem. 1995; 270: 5872-76.
Amaral TMS, Macedo D, Fernandes I, Costa L. Castration-resistant prostate cancer: mechanisms, targets, and treatment. Prostate Cancer. 2012; 2012: 327253.
Bernhard EJ, Gruber SB, Muschel RJ. Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci USA. 1994; 91: 4293-97.
Bjornland K, Flatmark K, Pettersen S, Aaasen AO, Fodstad O, Maelandsmo GM. Matrix metalloproteinases participate in osteosarcoma invasion. J Surg Res. 2005; 127: 151-56.
Borradaile NM, Carroll KK, Kurowska EM. Regulation of HepG2 cell apolipoprotein B metabolism by the citrus fruit flavanones hesperetin and naringenin. Lipids 1999; 34: 591-98.
Bosetti C, Spertini L, Parpinel M, Gnagnarella P, Lagiou P, Negri E, Franceschi S, Montella M, Peterson J, Dwyer J, Giacosa A, La Vecchia C. Flavonoids and breast cancer risk in Italy. Cancer Epidemiol Biomarkers Prev. 2005; 14: 805-08.
Cavia-Saiz M, Busto MD, Pilar-Izquierdo MC, Ortega N, Perez-Mateos M, Muñiz P. Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study. J Sci Food Agric. 2010; 90: 1238-44.
Chen PS, Shih YW, Huang HC, Cheng H-W. Diosgenin, a steroidal saponin, inhibits migration and invasion of human prostate cancer PC-3 cells by reducing matrix metalloproteinases expression. PLoS One. 2011; 6: e20164.
Chen HJ, Lin CM, Lee CY, Shih NC, Peng SF, Tsuzuki M, Amagaya S, Huang WW, Yang JS. Kaempferol suppresses cell metastasis via inhibition of the ERK-p38-JNK and AP-1 signaling pathways in U-2 OS human osteosarcoma cells. Oncol Rep. 2013; 30: 925-32.
Cheng F, Breen K. On the ability of four flavonoids, baicilein, luteolin, naringenin and quercetin, to suppress the fenton reaction of the iron ATP complex. BioMet. 2000; 13: 77-83.
Chiang JH, Yang JS, Ma CY, Yang MD, Huang HY, Hsia TC, Kuo HM, Wu PP, Lee TH, Chung JG. Danthron, an anthraquinone derivative, induces DNA damage and caspase cascades-mediated apoptosis in SNU-1 human gastric cancer cells through mitochondrial permeability transition pores and Bax-triggered pathways. Chem Res Toxicol. 2011; 24: 20-29.
Chien CS, Shen KH, Huang JS, Ko SC, Shih YW. Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with down regulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem. 2010; 333: 169-80.
Emmert-Buck MR, Roth MJ, Zhuang Z, Campo E, Rozhin J, Sloane BF, Liotta LA, Stetler-Stevenson WG. Increased gelatinase A (MMP-2) and cathepsin B activity in invasive tumor regions of human colon cancer samples. Am J Pathol. 1994; 145: 1285-90.
Fang Z, Tang Y, Fang J, Zhou Z, Xing Z, Guo Z, Guo X, Wang W, Jiao W, Xu Z, Liu Z. Simvastatin inhibits renal cancer cell growth and metastasis via AKT/mTOR, ERK and JAK2/STAT3 pathway. PLoS One. 2013; 8: e62823.
Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001; 1: 34-45.
Gullu IH, Kurdoglu M, Akalin I. The relation of gelatinase (MMP-2 and -9) expression with distant site metastasis and tumour aggressiveness in colorectal cancer. Br J Cancer. 2000; 82: 249.
Guruvayoorappan C, Kuttan G. Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, STAT-1, NM23 and cytokines in lung tissues of C57BL/6 mice. Immunopharmacol Immunotoxicol. 2008; 30: 711-27.
Hermenean A, Ardelean A, Stan M, Hadaruga N, Mihali CV, Costache M, Dinischiotu A. Antioxidant and hepatoprotective effects of naringenin and its ?-cyclodextrin formulation in mice intoxicated with carbon tetrachloride: A comparative study. J Med Food. 2014; 17: 670-77.
Huang YB, Lin MW, Chao Y, Huang CT, Tsai YH, Wu PC. Anti-oxidant activity and attenuation of bladder hyperactivity by the flavonoid compound kaempferol. Int J Urol. 2014; 21: 94-98.
Hwang ES, Park KK. Magnolol suppresses metastasis via inhibition of invasion, migration, and matrix metalloproteinase-2/-9 activities in PC-3 human prostate carcinoma cells. Biosci Biotechnol Biochem. 2010; 74: 961-67.
Itoh Y, Nagase H. Matrix metalloproteinases in cancer. Essays Biochem. 2002; 38: 21-36.
Jemal A, Bray F, Center MM, Ferlay J,Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61: 69-90.
Kahari V, Saarialho-Kere U. Matrix metalloproteinases and their inhibitors in tumour growth and invasion. Ann Med. 1999; 31: 34-45.
Kang JW, Kim JH, Song K, Kim SH, Yoon JH, Kim KS. Kaempferol and quercetin, components of Ginkgo biloba extract (EGb 761), induce caspase-3- dependent apoptosis in oral cavity cancer cells. Phytother Res. 2010; 24: S77-S82.
Kilian M, Gregor JI, Heukamp I, Hanel M, Ahlgrimm M, Schimke I, Kristiansen G, Ommer A, Walz MK, Jacobi CA, Wenger FA. Matrix metalloproteinase inhibitor RO 28-2653 decreases liver metastasis by reduction of MMP-2 and MMP-9 concentration in BOP-induced ductal pancreatic cancer in Syrian Hamsters: Inhibition of matrix metalloproteinases in pancreatic cancer. Prostaglandins Leukot Essent Fatty Acids. 2006; 75: 429-34.
Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS, Chung J. Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J. 2001; 15: 1953-62.
Kong D, Li Y,Wang Z, Banerjee S, Sarkar FH. Inhibition of angiogenesis and invasion by 3,3?-diindolylmethane ismediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res. 2007; 67: 3310-19.
Limtrakul P, Khantamat O, Pintha K. Inhibition of P-glycoprotein activity and reversal of cancer multidrug resistance by Momordica charantia extract. Cancer Chemother Pharmacol. 2004; 54: 525-30.
Lin CW, Chen PN, Chen MK, Yang WE, Yang CHTS, Hsieh YS. Kaempferol reduces matrix metalloproteinase-2 expression by down-regulating ERK1/2 and the activator protein-1 signaling pathways in oral cancer cells. PLoS One. 2013; 8: e80883.
Liu KC, Huang AC, Wu PP, Lin HY, Chueh FS, Yang JS, Lu CC, Chiang JH, Meng M, Chung JG. Gallic acid suppresses the migration and invasion of PC-3 human prostate cancer cells via inhibition of matrix metalloproteinase-2 and -9 signaling pathways. Oncol Rep. 2011; 26: 177-84.
Lu HR, Zhu H, Huang M, Chen Y, Cai YJ, Miao ZH, Zhang JS, Ding J. Reactive oxygen species elicit apoptosis by concurrently disrupting topoisomerase II and DNA-dependent protein kinase. Mol Pharmacol. 2005; 68: 983-94.
Lu CC, Yang JS, Huang AC, Hsia TC, Chou ST, Kuo CL, Lu HF, Lee TH, Wood WG, Chung JG. Chrysophanol induces necrosis through the production of ROS and alteration of ATP levels in J5 human liver cancer cells. Mol Nutr Food Res. 2010; 54: 967?76.
Manthey JA, Guthrie N, Grohmann K. Biological properties of citrus flavonoids pertaining to cancer and inflammation. Curr Med Chem. 2001; 8: 135-53.
Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong CP, Nettleton JA, Jacobs DR Jr. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr. 2007; 85: 895-909.
Mizutani K, Kofuji K, Shirouzu K. The significance of MMP-1 and MMP-2 in peritoneal disseminated metastasis of gastric cancer. Surg Today. 2000; 30: 614-21.
Mook OR, Frederiks WM, Van Noorden CJ. The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta. 2004; 1705: 69-89.
Mulvihill EE, Assini JM, Sutherland BG, DiMattia AS, Khami M, Koppes JB, Sawyez CG, Whitman SC, Huff MW. Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice. Arterioscler Thromb Vasc Biol. 2010; 30: 742-48.
Nemeth JA, Yousif R, Herzog M, Che M, Upadhyay J, Shekarriz B, Bhagat S, Mullins C, Fridman R, Cher ML. Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis. J Natl Cancer Inst. 2002; 94: 17-25.
Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren K, van Leeuwen PA. Flavonoids: A review of probable mechanisms of action and potential applications. Am J Clin Nutr. 2001; 74: 418-25.
Okada Y, Gonoji Y, Naka K, Tomita K, Nakanishi I, Iwata K, Yamashita K, Hayakawa T. Matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) from HT 1080 human fibrosarcoma cells. Purification and activation of the precursor and enzymic properties. J Biol Chem. 1992; 267: 12-19.
Roberts PJ, Der CJ. Targeting the RafMEKERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007; 26: 3291-10.
Rossi M, Negri E, Talamini R, Bosetti C, Parpinel M, Gnagnarella P, Franceschi S, Dal Maso L, Montella M, Giacosa A, La Vecchia C. Flavonoids and colorectal cancer in Italy. Cancer Epidemiol Biomarkers Prev. 2006; 15: 1555-58.
Ruh MF, Zacharewsky T, Connor K, Howell J, Chen I, Safe S. Naringenin: a weakly estrogenic bioflavonoid that exhibits antiestrogenic activity. Biochem Phamacol. 1995; 50: 1485-93.
Schor SL, Allen TD, Harrison CJ. Cell migration through three dimensional gels of native collagen fibres: Collagenolytic activity is not required for the migration of two permanent cell lines. J Cell Sci. 1980; 46: 171-86.
Shukla S, MacLennan GT, Hartman DJ, Fu P, Resnick MI, Gupta S. Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer. 2007; 121: 1424-32.
Simpson-Haidaris P, Rybarczyk B. Tumors and fibrinogen. Ann NY Acad Sci. 2001; 936: 406-25.
Stearns M, Stearns ME. Evidence for increased activated metalloproteinase 2 (MMP-2a) expression associated with human prostate cancer progression. Oncol Res. 1995; 8: 69-75.
Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, Donia M, Fagone P, Malaponte G, Nicoletti F, Libra M, Milella M, Tafuri A, Bonati A, Bäsecke J, Cocco L, Evangelisti C, Martelli AM, Montalto G, Cervello M, McCubrey JA. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging 2011; 3: 192
Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer. 2003; 3: 768-80.
Weng CJ, Yen GC. Flavonoids, a ubiquitous dietary phenolic subclass, exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Cancer Metastasis Rev. 2012; 31: 323-51.
Zhang L, Shi J, Feng J, Klocker H, Lee C and Zhang J. Type IVcollagenase (matrix metalloproteinase-2 and -9) in prostate cancer. Prostate Cancer Prostatic Dis. 2004; 7: 327-32.
Zhou J, Chen Y, Lang JY, Lu JJ, Ding J. Salvicine inactivates beta 1 integrin and inhibits adhesion of MDA-MB-435 cells to fibronectin via reactive oxygen species signaling. Mol Cancer Res. 2008; 6: 194-204.
Zucker S, Vacirca J. Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev. 2004; 23: 101-17.
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