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BMC Cancer
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells

Authors: Yun-Hee Rhee, Soo-Jin Jeong, Hyo-Jeong Lee, Hyo-Jung Lee, Wonil Koh, Ji Hoon Jung, Sun-Hee Kim, Kim Sung-Hoon

Published in: BMC Cancer | Issue 1/2012

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Abstract

Background

Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells.

Results

Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control.

Conclusion

These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells.
Appendix
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Literature
1.
Kim DS, Baek NI, Oh SR, Jung KY, Lee IS, Kim JH, Lee HK: Anticomplementary activity of ergosterol peroxide fromNaematoloma fasciculare and reassignment of NMR data. Arch Pharm Res. 1997, 20 (3): 201-205. 10.1007/BF02976145.CrossRefPubMed
2.
Piovano M, Guzman G, Garbarino JA, Chamy MC: The chemistry of Bacidia stipata (Lichens, Ascomycotina). Biochem System Ecol. 1999, 27: 663-664. 10.1016/S0305-1978(98)00120-3.CrossRef
3.
Arisawa M, Fujita A, Saga M, Fukumura H, Hayashi T, Shimizu M, Morita N: Three new lanostanoids from Ganoderma lucidum. J Nat Prod. 1986, 49 (4): 621-625. 10.1021/np50046a010.CrossRefPubMed
4.
Sgarbi DB, da Silva AJ, Carlos IZ, Silva CL, Angluster J, Alviano CS: Isolation of ergosterol peroxide and its reversion to ergosterol in the pathogenic fungus Sporothrix schenckii. Mycopathologia. 1997, 139 (1): 9-14. 10.1023/A:1006803832164.CrossRefPubMed
5.
Bok JW, Lermer L, Chilton J, Klingeman HG, Towers GH: Antitumor sterols from the mycelia of Cordyceps sinensis. Phytochemistry. 1999, 51 (7): 891-898. 10.1016/S0031-9422(99)00128-4.CrossRefPubMed
6.
Lindequist U, Teuscher E, Wolf B, Volsgen A, Hoffmann S, Kutschabsky L, Franke P, Seefeldt R: [Isolation, characterization and structure elucidation of a substance with immunosuppressive action from Tricholoma populinum Lange]. Pharmazie. 1989, 44 (2): 165-PubMed
7.
Fujimoto H, Nakayama M, Nakayama Y, Yamazaki M: Isolation and characterization of immunosuppressive components of three mushrooms, Pisolithus tinctorius, Microporus flabelliformis and Lenzites betulina. Chem Pharm Bull (Tokyo). 1994, 42 (3): 694-697. 10.1248/cpb.42.694.CrossRef
8.
Kreisel H, Lindequist U, Horak M: Distribution, ecology, and immunosuppressive properties of Tricholoma populinum (Basidiomycetes). Zentralbl Mikrobiol. 1990, 145 (5): 393-396.PubMed
9.
Lindequist U, Lesnau A, Teuscher E, Pilgrim H: [The antiviral action of ergosterol peroxide]. Pharmazie. 1989, 44 (8): 579-580.PubMed
10.
Yasukawa K, Akihisa T, Kanno H, Kaminaga T, Izumida M, Sakoh T, Tamura T, Takido M: Inhibitory effects of sterols isolated from Chlorella vulgaris on 12-0-tetradecanoylphorbol-13-acetate-induced inflammation and tumor promotion in mouse skin. Biol Pharm Bull. 1996, 19 (4): 573-576. 10.1248/bpb.19.573.CrossRefPubMed
11.
Darnell JE: STATs and gene regulation. Science. 1997, 277 (5332): 1630-1635. 10.1126/science.277.5332.1630.CrossRefPubMed
12.
Ihle JN: Cytokine receptor signalling. Nature. 1995, 591-594. 377
13.
Zhong Z, Wen Z, Darnell JE: Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994, 264 (5155): 95-98. 10.1126/science.8140422.CrossRefPubMed
14.
Bharti AC, Donato N, Aggarwal BB: Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol. 2003, 171 (7): 3863-3871.CrossRefPubMed
15.
Buettner R, Mora LB, Jove R: Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002, 8 (4): 945-954.PubMed
16.
Schreiner SJ, Schiavone AP, Smithgall TE: Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. J Biol Chem. 2002, 277 (47): 45680-45687. 10.1074/jbc.M204255200.CrossRefPubMed
17.
Kim ES, Hong SY, Lee HK, Kim SW, An MJ, Kim TI, Lee KR, Kim WH, Cheon JH: Guggulsterone inhibits angiogenesis by blocking STAT3 and VEGF expression in colon cancer cells. Oncol Rep. 2008, 20 (6): 1321-1327.PubMed
18.
Lin CM, Shyu KG, Wang BW, Chang H, Chen YH, Chiu JH: Chrysin suppresses IL-6-induced angiogenesis via down-regulation of JAK1/STAT3 and VEGF: an in vitro and in ovo approach. J Agric Food Chem. 2010, 58 (11): 7082-7087. 10.1021/jf100421w.CrossRefPubMed
19.
Chen Z, Han ZC: STAT3: a critical transcription activator in angiogenesis. Med Res Rev. 2008, 28 (2): 185-200. 10.1002/med.20101.CrossRefPubMed
20.
Krzyczkowskia W, Malinowska E, Suchocki P, Kleps J, Olejnik M, Herold F: Isolation and quantitative determination of ergosterol peroxide in various edible mushroom species. Food Chemistry. 2009, 113 (1): 351-355. 10.1016/j.foodchem.2008.06.075.CrossRef
21.
Jaffe EA, Nachman RL, Becker CG, Minick CR: Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973, 52 (11): 2745-2756. 10.1172/JCI107470.CrossRefPubMedPubMedCentral
22.
Yu CL, Meyer DJ, Campvell GS: Enhanced DNA-binding activity of a stat3-regulated protein in cells transformed by the src oncoprotein. Science. 1995, 269: 81-83. 10.1126/science.7541555.CrossRefPubMed
23.
Grant DS, Kinsella JL, Fridman R, Auerbach R, Piasecki BA, Yamada Y, Zain M, Kleinman HK: Interaction of endothelial cells with a laminin A chain peptide (SIKVAV) in vitro and induction of angiogenic behavior in vivo. J Cell Physiol. 1992, 153 (3): 614-625. 10.1002/jcp.1041530324.CrossRefPubMed
24.
Ihle JN: STATs: signal transducers and activators of transcription. Cell. 1996, 84: 331-334. 10.1016/S0092-8674(00)81277-5.CrossRefPubMed
25.
Oka T, Ouchida M, Koyama M, Ogama Y, Takada S, Nakatani Y, Tanaka T, Yoshino T, Hayashi K, Ohara N, et al: Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res. 2002, 62 (22): 6390-6394.PubMed
26.
Han Y, Amin HM, Franko B, Frantz C, Shi X, Lai R: Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. Blood. 2006, 108 (8): 2796-2803. 10.1182/blood-2006-04-017434.CrossRefPubMed
27.
Wu C, Sun M, Liu L, Zhou GW: The function of the protein tyrosine phosphatase SHP-1 in cancer. Gene. 2003, 306: 1-12.CrossRefPubMed
28.
Wang Z, Luo F, Li L, Yang L, Hu D, Ma X, Lu Z, Sun L, Cao Y: STAT3 activation induced by Epstein-Barr virus latent membrane protein1 causes vascular endothelial growth factor expression and cellular invasiveness via JAK3 And ERK signaling. Eur J Cancer. 2010, 46 (16): 2996-3006. 10.1016/j.ejca.2010.07.008.CrossRefPubMed
29.
Yu H, Jove R: The STATs of cancer--new molecular targets come of age. Nat Rev Cancer. 2004, 4 (2): 97-105. 10.1038/nrc1275.CrossRefPubMed
30.
Ebrahem Q, Minamoto A, Hoppe G, Anand-Apte B, Sears JE: Triamcinolone acetonide inhibits IL-6- and VEGF-induced angiogenesis downstream of the IL-6 and VEGF receptors. Invest Ophthalmol Vis Sci. 2006, 47 (11): 4935-4941. 10.1167/iovs.05-1651.CrossRefPubMed
31.
Haematology: UmfBCfSi: Diagnosis and management of multiple myeloma. Br J Haematol. 2001, 115 (3): 522-540.CrossRef
32.
Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, Nair AS, Shishodia S, Aggarwal BB: Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 2007, 109 (6): 2293-2302. 10.1182/blood-2006-02-003988.CrossRefPubMed
33.
Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, Aggarwal BB: Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res. 2007, 13 (10): 3024-3032. 10.1158/1078-0432.CCR-06-2575.CrossRefPubMed
34.
Lee JC, Ahn KS, Jeong SJ, Jung JH, Kwon TR, Rhee YH, Kim SH, Kim SY, Yoon HJ, Zhu S, et al: Signal transducer and activator of transcription 3 pathway mediates genipin-induced apoptosis in U266 multiple myeloma cells. J Cell Biochem. 2011.
35.
Kim SH, Ahn KS, Jeong SJ, Kwon TR, Jung JH, Yun SM, Han I, Lee SG, Kim DK, Kang M, et al: Janus activated kinase 2/signal transducer and activator of transcription 3 pathway mediates icariside II-induced apoptosis in U266 multiple myeloma cells. Eur J Pharmacol. 2011, 654 (1): 10-16. 10.1016/j.ejphar.2010.11.032.CrossRefPubMed
36.
Zhang DW, Cheng Y, Wang NL, Zhang JC, Yang MS, Yao XS: Effects of total flavonoids and flavonol glycosides from Epimedium koreanum Nakai on the proliferation and differentiation of primary osteoblasts. Phytomedicine. 2008, 15 (1-2): 55-61. 10.1016/j.phymed.2007.04.002.CrossRefPubMed
37.
Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, Garcia R, Bowman T, Falcone R, Fairclough R, Cantor A, et al: Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 2002, 62 (22): 6659-6666.PubMed
38.
Dolled-Filhart M, Camp RL, Kowalski DP, Smith BL, Rimm DL: Tissue microarray analysis of signal transducers and activators of transcription 3 (Stat3) and phospho-Stat3 (Tyr705) in node-negative breast cancer shows nuclear localization is associated with a better prognosis. Clin Cancer Res. 2003, 9 (2): 594-600.PubMed
39.
Nagpal JK, Mishra R, Das BR: Activation of Stat-3 as one of the early events in tobacco chewing-mediated oral carcinogenesis. Cancer. 2002, 94 (9): 2393-2400. 10.1002/cncr.10499.CrossRefPubMed
40.
Hsiao JR, Jin YT, Tsai ST, Shiau AL, Wu CL, Su WC: Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis. Br J Cancer. 2003, 89 (2): 344-349. 10.1038/sj.bjc.6601003.CrossRefPubMedPubMedCentral
41.
Takei T, Yoshida M, Ohnishi-Kameyama M, Kobori M: Ergosterol peroxide, an apoptosis-inducing component isolated from Sarcodon aspratus (Berk.) S. Ito. Biosci Biotechnol Biochem. 2005, 69 (1): 212-215. 10.1271/bbb.69.212.CrossRefPubMed
42.
Russo A, Cardile V, Piovano M, Caggia S, Espinoza CL, Garbarino JA: Pro-apoptotic activity of ergosterol peroxide and (22E)-ergosta-7, 22-dien-5alpha-hydroxy-3, 6-dione in human prostate cancer cells. Chem Biol Interact. 2010, 184 (3): 352-358. 10.1016/j.cbi.2010.01.032.CrossRefPubMed
43.
Kobori M, Yoshida M, Ohnishi-Kameyama M, Shinmoto H: Ergosterol peroxide from an edible mushroom suppresses inflammatory responses in RAW264.7 macrophages and growth of HT29 colon adenocarcinoma cells. Br J Pharmacol. 2007, 150 (2): 209-219. 10.1038/sj.bjp.0706972.CrossRefPubMed
44.
Chen YK, Kuo YH, Chiang BH, Lo JM, Sheen LY: Cytotoxic activities of 9, 11-dehydroergosterol peroxide and ergosterol peroxide from the fermentation mycelia of ganoderma lucidum cultivated in the medium containing leguminous plants on Hep 3B cells. J Agric Food Chem. 2009, 57 (13): 5713-5719. 10.1021/jf900581h.CrossRefPubMed
45.
Tenev T, Bohmer SA, Kaufmann R, Frese S, Bittorf T, Beckers T, Bohmer FD: Perinuclear localization of the protein-tyrosine phosphatase SHP-1 and inhibition of epidermal growth factor-stimulated STAT1/3 activation in A431 cells. Eur J Cell Biol. 2000, 79 (4): 261-271. 10.1078/S0171-9335(04)70029-1.CrossRefPubMed
46.
Kim H, Baumann H: Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Mol Cell Biol. 1999, 19 (8): 5326-5338.CrossRefPubMedPubMedCentral
47.
Sun S, Steinberg BM: PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells. J Gen Virol. 2002, 83 (Pt 7): 1651-1658.CrossRefPubMed
48.
Norkina O, Dolganiuc A, Catalano D, Kodys K, Mandrekar P, Syed A, Efros M, Szabo G: Acute alcohol intake induces SOCS1 and SOCS3 and inhibits cytokine-induced STAT1 and STAT3 signaling in human monocytes. Alcohol Clin Exp Res. 2008, 32 (9): 1565-1573. 10.1111/j.1530-0277.2008.00726.x.CrossRefPubMedPubMedCentral
49.
Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, et al: Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 2002, 21 (13): 2000-2008. 10.1038/sj.onc.1205260.CrossRefPubMed
50.
Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, et al: Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 2003, 22 (3): 319-329. 10.1038/sj.onc.1206122.CrossRefPubMed
51.
Inoue S, Branch CD, Gallick GE, Chada S, Ramesh R: Inhibition of Src kinase activity by Ad-mda7 suppresses vascular endothelial growth factor expression in prostate carcinoma cells. Mol Ther. 2005, 12 (4): 707-715. 10.1016/j.ymthe.2005.05.015.CrossRefPubMed
52.
Kobori M, Yoshida M, Ohnishi-Kameyama M, Takei T, Shinmoto H: 5alpha,8alpha-Epidioxy-22E-ergosta-6, 9(11),22-trien-3beta-ol from an edible mushroom suppresses growth of HL60 leukemia and HT29 colon adenocarcinoma cells. Biol Pharm Bull. 2006, 29 (4): 755-759. 10.1248/bpb.29.755.CrossRefPubMed
Metadata
Title
Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells
Authors
Yun-Hee Rhee
Soo-Jin Jeong
Hyo-Jeong Lee
Hyo-Jung Lee
Wonil Koh
Ji Hoon Jung
Sun-Hee Kim
Kim Sung-Hoon
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-28

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