Morusin induces apoptosis by regulating expression of Bax and Survivin in human breast cancer cells

Kang,Sukmin; Kim,Eun‑Ok; Kim,Sung‑Hoon; Lee,Jun‑Hee; Ahn,Kwang  Seok; Yun,Miyong; Lee,Seok‑Geun

doi:10.3892/ol.2017.6006

Morusin induces apoptosis by regulating expression of Bax and Survivin in human breast cancer cells

Authors:
- Sukmin Kang
- Eun‑Ok Kim
- Sung‑Hoon Kim
- Jun‑Hee Lee
- Kwang Seok Ahn
- Miyong Yun
- Seok‑Geun Lee
View Affiliations

Affiliations: Department of Cancer Preventive Material Development, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea, Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea, Department of Sasang Constitutional Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
Published online on: April 7, 2017 https://doi.org/10.3892/ol.2017.6006
Pages: 4558-4562

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

Morusin which has been isolated from the root bark of Morus alba L. (Moraceae) has previously demonstrated anticancer activity in various types of cancer cells such as hepatocellular carcinoma, glioma and prostate cancer. However, the effect of morusin on breast cancer cells remains unclear. In the present study, the potential of morusin as an anti‑cancer agent in breast cancer was investigated. The results of the present study revealed that the treatment of morusin induced cell death in various human breast cancer cell lines, but exhibited little effect on normal human breast epithelial cells. In Annexin V‑propidium iodide double staining assays, morusin significantly increased apoptosis in a dose‑dependent manner in human breast cancer cells. The apoptosis marker proteins cleaved caspase 3 and 9 were consistently upregulated following treatment of cells with morusin in a time‑ and dose‑dependent manner. Furthermore, morusin was demonstrated to modulate the expression of the anti‑apoptotic protein Survivin and pro‑apoptotic protein B‑cell lymphoma 2‑associated‑x protein (Bax) in human breast cancer cells. These results indicate that morusin induces apoptosis by suppressing Survivin and inducing Bax proteins, suggesting that morusin is a potentially effective therapeutic agent for the treatment of patients with breast cancer.

View Figures

View References

1	Bellik Y, Boukraâ L, Alzahrani HA, Bakhotmah BA, Abdellah F, Hammoudi SM and Iguer-Ouada M: Molecular mechanism underlying anti-inflammatory and anti-allergic activities of phytochemicals: An update. Molecules. 18:322–353. 2012. View Article : Google Scholar : PubMed/NCBI
2	Fukai T, Satoh K, Nomura T and Sakagami H: Antinephritis and radical scavenging activity of prenylflavonoids. Fitoterapia. 74:720–724. 2003. View Article : Google Scholar : PubMed/NCBI
3	Sohn HY, Son KH, Kwon CS, Kwon GS and Kang SS: Antimicrobial and cytotoxic activity of 18 prenylated flavonoids isolated from medicinal plants: Morus alba L., Morus mongolica Schneider, Broussnetia papyrifera (L.) Vent, Sophora flavescens Ait and Echinosophora koreensis Nakai. Phytomedicine. 11:666–672. 2004. View Article : Google Scholar : PubMed/NCBI
4	Guo H, Liu C, Yang L, Dong L, Wang L, Wang Q, Li H, Zhang J, Lin P and Wang X: Morusin inhibits glioblastoma stem cell growth in vitro and in vivo through stemness attenuation, adipocyte transdifferentiation, and apoptosis induction. Mol Carcinog. 55:77–89. 2016. View Article : Google Scholar : PubMed/NCBI
5	Lee JC, Won SJ, Chao CL, Wu FL, Liu HS, Ling P, Lin CN and Su CL: Morusin induces apoptosis and suppresses NF-kappaB activity in human colorectal cancer HT-29 cells. Biochem Biophys Res Commun. 372:236–242. 2008. View Article : Google Scholar : PubMed/NCBI
6	Lim SL, Park SY, Kang S, Park D, Kim SH, Um JY, Jang HJ, Lee JH, Jeong CH, Jang JH, et al: Morusin induces cell death through inactivating STAT3 signaling in prostate cancer cells. Am J Cancer Res. 5:289–299. 2015.PubMed/NCBI
7	Lin WL, Lai DY, Lee YJ, Chen NF and Tseng TH: Antitumor progression potential of morusin suppressing STAT3 and NFκB in human hepatoma SK-Hep1 cells. Toxicol Lett. 232:490–498. 2015. View Article : Google Scholar : PubMed/NCBI
8	Wan LZ, Ma B and Zhang YQ: Preparation of morusin from Ramulus mori and its effects on mice with transplanted H22 hepatocarcinoma. Biofactors. 40:636–645. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wang L, Guo H, Yang L, Dong L, Lin C, Zhang J, Lin P and Wang X: Morusin inhibits human cervical cancer stem cell growth and migration through attenuation of NF-κB activity and apoptosis induction. Mol Cell Biochem. 379:7–18. 2013. View Article : Google Scholar : PubMed/NCBI
10	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
11	Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D and Bray F: Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur J Cancer. 49:1374–1403. 2013. View Article : Google Scholar : PubMed/NCBI
12	Kim Z, Min SY, Yoon CS, Lee HJ, Lee JS, Youn HJ, Park HK, Noh DY and Hur MH; Korean Breast Cancer Society, : The basic facts of korean breast cancer in 2011: Results of a nationwide survey and breast cancer registry database. J Breast Cancer. 17:99–106. 2014. View Article : Google Scholar : PubMed/NCBI
13	Thompson A, Brennan K, Cox A, Gee J, Harcourt D, Harris A, Harvie M, Holen I, Howell A, Nicholson R, et al: Evaluation of the current knowledge limitations in breast cancer research: A gap analysis. Breast Cancer Res. 10:R262008. View Article : Google Scholar : PubMed/NCBI
14	Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH and Lee JS: Prediction of cancer incidence and mortality in Korea, 2014. Cancer Res Treat. 46:124–130. 2014. View Article : Google Scholar : PubMed/NCBI
15	Park SK, Sakoda LC, Kang D, Chokkalingam AP, Lee E, Shin HR, Ahn YO, Shin MH, Lee CW, Lee DH, et al: Rising prostate cancer rates in South Korea. Prostate. 66:1285–1291. 2006. View Article : Google Scholar : PubMed/NCBI
16	Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB and Korsmeyer SJ: Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science. 292:727–730. 2001. View Article : Google Scholar : PubMed/NCBI
17	Bae SI, Park JG, Kim YI and Kim WH: Genetic alterations in gastric cancer cell lines and their original tissues. Int J Cancer. 87:512–516. 2000. View Article : Google Scholar : PubMed/NCBI
18	Meijerink JP, Mensink EJ, Wang K, Sedlak TW, Slöetjes AW, de Witte T, Waksman G and Korsmeyer SJ: Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood. 91:2991–2997. 1998.PubMed/NCBI
19	Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC and Perucho M: Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 275:967–969. 1997. View Article : Google Scholar : PubMed/NCBI
20	Altieri DC: Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene. 22:8581–8589. 2003. View Article : Google Scholar : PubMed/NCBI
21	Altieri DC: Validating survivin as a cancer therapeutic target. Nat Rev Cancer. 3:46–54. 2003. View Article : Google Scholar : PubMed/NCBI
22	Ambrosini G, Adida C and Altieri DC: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 3:917–921. 1997. View Article : Google Scholar : PubMed/NCBI
23	Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC and Altieri DC: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 396:580–584. 1998. View Article : Google Scholar : PubMed/NCBI
24	https://www.atcc.org/Products/All/CRL-10317.aspx#culturemethod
25	Park SY, Lim SL, Jang HJ, Lee JH, Um JY, Kim SH, Ahn KS and Lee SG: Embelin induces apoptosis in human glioma cells through inactivating NF-κB. J Pharmacol Sci. 121:192–199. 2013. View Article : Google Scholar : PubMed/NCBI
26	Dandawate PR, Subramaniam D, Jensen RA and Anant S: Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Semin Cancer Biol. 40–41. 192–208. 2016.PubMed/NCBI
27	Kotecha R, Takami A and Espinoza JL: Dietary phytochemicals and cancer chemoprevention: A review of the clinical evidence. Oncotarget. 7:52517–52529. 2016.PubMed/NCBI
28	Shankar E, Kanwal R, Candamo M and Gupta S: Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. Semin Cancer Biol. 40–41. 82–99. 2016.PubMed/NCBI
29	Du Toit A: Cell death: Balance through a bivalent regulator. Nat Rev Mol Cell Biol. 14:5462013. View Article : Google Scholar
30	Mohammad RM, Muqbil I, Lowe L, Yedjou C, Hsu HY, Lin LT, Siegelin MD, Fimognari C, Kumar NB, Dou QP, et al: Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol. 35 Suppl:S78–S103. 2015. View Article : Google Scholar : PubMed/NCBI
31	Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, et al: Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res. 12:11–19. 2006. View Article : Google Scholar : PubMed/NCBI
32	Nielsen M, Kaestel CG, Eriksen KW, Woetmann A, Stokkedal T, Kaltoft K, Geisler C, Röpke C and Odum N: Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells. Leukemia. 13:735–738. 1999. View Article : Google Scholar : PubMed/NCBI