Morin, a flavonoid from Moraceae, suppresses growth and invasion of the highly metastatic breast cancer cell line MDA-MB‑231 partly through suppression of the Akt pathway

Jin,Hana; Lee,Won  Sup; Eun,So  Young; Jung,Ji  Hyun; Park,Hyeon-Soo; Kim,Gonsup; Choi,Yung  Hyun; Ryu,Chung  Ho; Jung,Jin  Myung; Hong,Soon  Chan; Shin,Sung  Chul; Kim,Hye  Jung

doi:10.3892/ijo.2014.2535

Morin, a flavonoid from Moraceae, suppresses growth and invasion of the highly metastatic breast cancer cell line MDA-MB‑231 partly through suppression of the Akt pathway

Authors:
- Hana Jin
- Won Sup Lee
- So Young Eun
- Ji Hyun Jung
- Hyeon-Soo Park
- Gonsup Kim
- Yung Hyun Choi
- Chung Ho Ryu
- Jin Myung Jung
- Soon Chan Hong
- Sung Chul Shin
- Hye Jung Kim
View Affiliations

Affiliations: Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea, Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea, Institute of Life Science and School of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Republic of Korea, Department of Biochemistry, Dongeui University College of Oriental Medicine and Department of Biomaterial Control (BK21 program), Dongeui University Graduate School, Busan 614-052, Republic of Korea, Division of Applied Life Science (BK 21 Program), Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Republic of Korea, Department of Neurosurgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea, Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea, Department of Chemistry, Research Institute of Life Science, Gyeongsang National University, Jinju 660-701, Republic of Korea
Published online on: July 4, 2014 https://doi.org/10.3892/ijo.2014.2535
Pages: 1629-1637

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Morin, a flavonoid found in figs and other Moraceae, displays a variety of biological actions, such as anti-oxidant, anti-inflammatory and anti-carcinogenic. However, the anticancer effects of morin and in particular its anti-metastatic effects are not well known. Therefore, in the present study, we investigated the anticancer effects of morin on highly metastatic human breast cancer cells. Our results showed that morin significantly inhibited the colony forming ability of highly metastatic MDA-MB‑231 breast cancer cells from low doses (50 µM) without cytotoxicity. In addition, morin changed MDA-MB‑231 cell morphology from mesenchymal shape to epithelial shape and inhibited the invasion of MDA-MB‑231 cells in a dose-dependent manner. Morin decreased matrix metalloproteinase-9 (MMP-9) secretion and expression of the mesenchymal marker N-cadherin of MDA-MB‑231 cells, suggesting that morin might suppress the EMT process. Furthermore, morin significantly decreased the phosphorylation of Akt, and inhibition of the Akt pathway significantly reduced MDA-MB‑231 invasion. In an in vivo xenograft mouse model, morin suppressed MDA-MB‑231 cancer cell progression. Taken together, our findings suggest that morin exhibits an inhibitory effect on the cancer progression and EMT process of highly metastatic breast cancer cells at least in part through inhibiting Akt activation. This study provides evidence that morin may have anticancer effects against metastatic breast cancer.

View Figures

View References

1	Hayes DF, Isaacs C and Stearns V: Prognostic factors in breast cancer: current and new predictors of metastasis. J Mammary Gland Biol Neoplasia. 6:375–392. 2001. View Article : Google Scholar : PubMed/NCBI
2	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
3	Korean Breast Cancer Society. Korean breast cancer data of 1996. J Korean Surg Soc. 55:621–635. 1998.
4	Keen JC and Davidson NE: The biology of breast carcinoma. Cancer. 97:825–833. 2003. View Article : Google Scholar : PubMed/NCBI
5	Anandappa SY, Sibson R, Platt-Higgins A, Winstanley JH, Rudland PS and Barraclough R: Variant estrogen receptor α mRNAs in human breast cancer specimens. Int J Cancer. 88:209–216. 2000.
6	Mostert B, Sleijfer S, Foekens JA and Gratama JW: Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer. Cancer Treat Rev. 35:463–474. 2009. View Article : Google Scholar : PubMed/NCBI
7	Yugarani T, Tan BKH, The M and Das NP: Effects of polyphenolic natural products on the lipid profiles of rats fed high fat diets. Lipids. 27:181–186. 1992. View Article : Google Scholar : PubMed/NCBI
8	Wu TW, Zeng LH, Wu J and Fung KP: Morin: a wood pigment that protects three types of human cells in the cardiovascular system against oxyradical damage. Biochem Pharmacol. 47:1099–1103. 1994. View Article : Google Scholar : PubMed/NCBI
9	Kleijnen J and Knipschild P: Ginkgo biloba. Lancet. 340:1136–1139. 1992. View Article : Google Scholar
10	McGregor D: Diets, food components and human cancer. Biotherapy. 11:189–200. 1998. View Article : Google Scholar : PubMed/NCBI
11	Robak J and Gryglewski RJ: Flavonoids are scavengers of superoxide anion. Biochem Pharmacol. 37:83–88. 1998.
12	Husain SR, Cillard J and Cillard P: Hydroxyl radical scavenging activity of flavonoids. Phytochemistry. 26:2489–2492. 1987. View Article : Google Scholar
13	Stavric B: Role of chemopreventers in human diet. Clin Biochem. 27:319–332. 1994. View Article : Google Scholar : PubMed/NCBI
14	Chang LW, Juang LJ, Wang BS, Wang MY, Tai HM, Hung WJ, Chen YJ and Huang MH: Antioxidant and antityrosinase activity of mulberry (Morus alba L.) twigs and root bark. Food Chem Toxicol. 49:785–790. 2011. View Article : Google Scholar : PubMed/NCBI
15	Ramanathan L, Das NP and Li QT: Studies on lipid oxidation in fish phospholipid liposomes. Biol Trace Elem Res. 40:59–70. 1994. View Article : Google Scholar : PubMed/NCBI
16	Hanasaki Y, Ogawaa S and Fukui S: The correlation between active oxygens scavenging and antioxidative effects of flavonoids. Free Radic Biol Med. 16:845–850. 1994. View Article : Google Scholar : PubMed/NCBI
17	Nakadate T, Yamamoto S, Aizu E and Kato R: Effects of flavonoids and antioxidants on 12-O-tetradecanoylphorbol-13-acetate-caused epidermal ornithine decarboxylase induction and tumor promotion in relation to lipoxygenase inhibition by these compounds. Gann. 75:214–222. 1984.
18	Baumann J, Bruchhausen FV and Wurm G: Flavonoids and related compounds as inhibitors of arachidonic acid peroxidation. Prostaglandins. 20:627–639. 1980. View Article : Google Scholar
19	Francis AR, Shetty TK and Bhattacharya RK: Modulating effect of plant flavonoids on the mutagenicity of N-methyl-N′-nitro-N-nitrosoguanidine. Carcinogenesis. 10:1953–1955. 1989.PubMed/NCBI
20	Huang MT, Wood AW, Newmark HL, Sayer JM, Yagi H, Jerina DM and Conney AH: Inhibition of the mutagenicity of bay-region diol-epoxides of polycyclic aromatic hydrocarbons by phenolic plant flavonoids. Carcinogenesis. 4:1631–1637. 1983. View Article : Google Scholar : PubMed/NCBI
21	Denda A, Ura H, Tsujiuchi T, Tsutsumi M, Eimoto H, Takashima Y, Kitazawa S, Kinugasa T and Konishi Y: Possible involvement of arachidonic acid metabolism in phenobarbital promotion of hepatocarcinogenesis. Carcinogenesis. 10:1929–1935. 1989. View Article : Google Scholar : PubMed/NCBI
22	Jin H, Lee WS, Yun JW, Jung JH, Lee SM, Kim HJ, Choi YH, Kim GS, Jung JM, Ryu CH, Shin SC and Hong SC: Flavonoids from Citrus unshiu Marc. inhibit cancer cell adhesion to endothelial cells by selective inhibition of VCAM-1. Oncol Rep. 30:2336–2342. 2013.
23	Vihinen P and Kahari VM: Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer. 99:157–166. 2002. View Article : Google Scholar : PubMed/NCBI
24	Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25:9–34. 2006. View Article : Google Scholar
25	Radisky ES and Radisky DC: Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer. J Mammary Gland Biol Neoplasia. 15:201–212. 2010. View Article : Google Scholar : PubMed/NCBI
26	Lelongt B, Trugnan G, Murphy G and Ronco PM: Matrix metalloproteinases MMP2 and MMP9 are produced in early stages of kidney morphogenesis but only MMP9 is required for renal organogenesis in vitro. J Cell Biol. 136:1363–1373. 1997. View Article : Google Scholar : PubMed/NCBI
27	Sarén P, Welgus HG and Kovanen PT: TNF-alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol. 157:4159–4165. 1996.PubMed/NCBI
28	Przybylowska K, Kluczna A, Zadrozny M, Krawczyk T, Kulig A, Rykala J, Kolacinska A, Morawiec Z, Drzewoski J and Blasiak J: Polymorphisms of the promoter regions of matrix metalloproteinases genes MMP-1 and MMP-9 in breast cancer. Breast Cancer Res Treat. 95:65–72. 2006. View Article : Google Scholar : PubMed/NCBI
29	Steeg PS: Cancer: micromanagement of metastasis. Nature. 449:671–673. 2007. View Article : Google Scholar : PubMed/NCBI
30	Steeg PS: Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 12:895–904. 2006. View Article : Google Scholar : PubMed/NCBI
31	Eccles SA and Welch DR: Metastasis: recent discoveries and novel treatment strategies. Lancet. 369:1742–1757. 2007. View Article : Google Scholar : PubMed/NCBI
32	White ES, Strom SR, Wys NL and Arenberg DA: Non-small cell lung cancer cells induce monocytes to increase expression of angiogenic activity. J Immunol. 166:7549–7555. 2001. View Article : Google Scholar : PubMed/NCBI
33	Ueno T, Toi M, Saji H, Muta M, Bando H, Kuroi K, Koike M, Inadera H and Matsushima K: Significance macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res. 6:3282–3289. 2000.PubMed/NCBI
34	Naylor MS, Stamp GW, Davies BD and Balkwill FR: Expression and activity of MMPS and their regulators in ovarian cancer. Int J Cancer. 58:50–56. 1994. View Article : Google Scholar : PubMed/NCBI
35	Kessenbrock K, Plaks V and Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 141:52–67. 2010. View Article : Google Scholar : PubMed/NCBI
36	Wu ZS, Wu Q, Yang JH, Wang HQ, Ding XD, Yang F and Xu XC: Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer. Int J Cancer. 122:2050–2056. 2008. View Article : Google Scholar : PubMed/NCBI
37	Suyama K, Shapiro I, Guttman M and Hazan RB: A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell. 2:301–314. 2002. View Article : Google Scholar : PubMed/NCBI
38	Hulit J, Suyama K, Chung S, Keren R, Agiostratidou G, Shan W, Dong X, Williams TM, Lisanti MP, Knudsen K and Hazan RB: N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. Cancer Res. 67:3106–3116. 2007. View Article : Google Scholar
39	Nagi C, Guttman M, Jaffer S, Qiao R, Keren R, Triana A, Li M, Godbold J, Bleiweiss IJ and Hazan RB: N-cadherin expression in breast cancer: correlation with an aggressive histologic variant--invasive micropapillary carcinoma. Breast Cancer Res Treat. 94:225–235. 2005. View Article : Google Scholar
40	Walsh MM and Bleiweiss IJ: Invasive micropapillary carcinoma of the breast: eighty cases of an underrecognized entity. Hum Pathol. 32:583–589. 2001. View Article : Google Scholar : PubMed/NCBI
41	Ho AT, Voura EB, Soloway PD, Watson KL and Khokha R: MMP inhibitors augment fibroblast adhesion through stabilization of focal adhesion contacts and up-regulation of cadherin function. J Biol Chem. 276:40215–40224. 2001. View Article : Google Scholar
42	Covington MD, Burghardt RC and Parrish AR: Ischemia-induced cleavage of cadherins in NRK cells requires MT1-MMP (MMP-14). Am J Physiol Renal Physiol. 290:F43–F51. 2006. View Article : Google Scholar : PubMed/NCBI
43	Pon YL, Auersperg N and Wong AS: Gonadotropins regulate N-cadherin mediated human ovarian surface epithelial cell survival at both posttranslational and transcriptional levels through a cyclic AMP/protein kinase A pathway. J Biol Chem. 280:15438–15448. 2005. View Article : Google Scholar
44	Yoon SO, Shin S, Lee HJ, Chun HK and Chung AS: Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression. Mol Cancer Ther. 5:2666–2675. 2006. View Article : Google Scholar : PubMed/NCBI
45	Chung TW, Lee YC and Kim CH: Hepatitis B viral HBx induces matrix metallo-proteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J. 18:1123–1125. 2004.PubMed/NCBI