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Erschienen in: Tumor Biology 9/2016

02.04.2016 | Original Article

25-methoxyl-dammarane-3β, 12β, 20-triol and artemisinin synergistically inhibit MDA-MB-231 cell proliferation through downregulation of testes-specific protease 50 (TSP50) expression

verfasst von: Danfeng Wang, Yuqing Zhao, Yimeng Wang, Yan Rong, Hongshuang Qin, Yongli Bao, Zhenbo Song, Chunlei Yu, Luguo Sun, Yuxin Li

Erschienen in: Tumor Biology | Ausgabe 9/2016

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Abstract

While the incidence of cancer continues to increase, the current therapeutic options remain imperfect. Therefore, there is an urgent need to discover new targeted anti-cancer therapies. Testes-specific protease 50 (TSP50) is abnormally expressed in most cancer tissues and downregulation of TSP50 expression can reduce cell proliferation and induce cell apoptosis, which makes it a potential target for cancer therapy. In this study, we constructed a firefly luciferase reporter pGL3-TSP50-3′-UTR as a drug screening model to screen potential candidate compounds that target TSP50 mRNA. We identified the compound 7P3A, which consists of 70 % 25-methoxyl-dammarane-3β, 12β, 20-triol and 30 % artemisinin, as being capable of inhibiting the TSP50-3′-UTR reporter activity, as well as the expression of TSP50. Further investigation revealed that 7P3A could inhibit MDA-MB-231 cell proliferation and induce cell cycle arrest, and over-expression of TSP50 partially reversed the effect of 7P3A. In vivo investigation showed that 7P3A could inhibit tumor growth in a xenograft model of breast cancer. These results suggest that 7P3A exhibits anti-cancer effects, in part, through downregulation of TSP50 expression.
Literatur
1.
Zurück zum Zitat Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. Ca-Cancer J Clin. 2011;61:69–90.CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. Ca-Cancer J Clin. 2011;61:69–90.CrossRefPubMed
2.
3.
Zurück zum Zitat Azim HA, Ibrahim AS. Breast cancer in Egypt, China and Chinese: statistics and beyond. J Thorac Dis. 2014;6:864–6.PubMedPubMedCentral Azim HA, Ibrahim AS. Breast cancer in Egypt, China and Chinese: statistics and beyond. J Thorac Dis. 2014;6:864–6.PubMedPubMedCentral
4.
Zurück zum Zitat DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and survivorship statistics, 2014. Ca-Cancer J Clin. 2014;64:252–71.CrossRefPubMed DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and survivorship statistics, 2014. Ca-Cancer J Clin. 2014;64:252–71.CrossRefPubMed
5.
Zurück zum Zitat Yuan L, Shan J, De Risi D, Broome J, Lovecchio J, Gal D, et al. Isolation of a novel gene, TSP50, by a hypomethylated DNA fragment in human breast cancer. Cancer Res. 1999;59:3215–21.PubMed Yuan L, Shan J, De Risi D, Broome J, Lovecchio J, Gal D, et al. Isolation of a novel gene, TSP50, by a hypomethylated DNA fragment in human breast cancer. Cancer Res. 1999;59:3215–21.PubMed
6.
Zurück zum Zitat Xu HP, Yuan L, Shan J, Feng H. Localization and expression of TSP50 protein in human and rodent testes. Urology. 2004;64:826–32.CrossRefPubMed Xu HP, Yuan L, Shan J, Feng H. Localization and expression of TSP50 protein in human and rodent testes. Urology. 2004;64:826–32.CrossRefPubMed
7.
Zurück zum Zitat Xu H, Shan J, Jurukovski V, Yuan L, Li J, Tian K. TSP50 encodes a testis-specific protease and is negatively regulated by p53. Cancer Res. 2007;67:1239–45.CrossRefPubMed Xu H, Shan J, Jurukovski V, Yuan L, Li J, Tian K. TSP50 encodes a testis-specific protease and is negatively regulated by p53. Cancer Res. 2007;67:1239–45.CrossRefPubMed
8.
Zurück zum Zitat Shan J, Yuan L, Xiao Q, Chiorazzi N, Budman D, Teichberg S, et al. TSP50, a possible protease in human testes, is activated in breast cancer epithelial cells. Cancer Res. 2002;62:290–4.PubMed Shan J, Yuan L, Xiao Q, Chiorazzi N, Budman D, Teichberg S, et al. TSP50, a possible protease in human testes, is activated in breast cancer epithelial cells. Cancer Res. 2002;62:290–4.PubMed
9.
Zurück zum Zitat Song ZB, Bao YL, Zhang Y, Mi XG, Wu P, Wu Y, et al. Testes-specific protease 50 (TSP50) promotes cell proliferation through the activation of the nuclear factor kappaB (NF-kappaB) signalling pathway. Biochem J. 2011;436:457–67.CrossRefPubMed Song ZB, Bao YL, Zhang Y, Mi XG, Wu P, Wu Y, et al. Testes-specific protease 50 (TSP50) promotes cell proliferation through the activation of the nuclear factor kappaB (NF-kappaB) signalling pathway. Biochem J. 2011;436:457–67.CrossRefPubMed
10.
Zurück zum Zitat Zhou L, Bao YL, Zhang Y, Wu Y, Yu CL, Huang YX, et al. Knockdown of TSP50 inhibits cell proliferation and induces apoptosis in P19 cells. IUBMB Life. 2010;62:825–32.CrossRefPubMed Zhou L, Bao YL, Zhang Y, Wu Y, Yu CL, Huang YX, et al. Knockdown of TSP50 inhibits cell proliferation and induces apoptosis in P19 cells. IUBMB Life. 2010;62:825–32.CrossRefPubMed
11.
Zurück zum Zitat Song ZB, Liu B, Li YY, Wu P, Bao YL, Huang YX, et al. The catalytic triad of testes-specific protease 50 (TSP50) is essential for its function in cell proliferation. Cell Signal. 2014;26:2266–75.CrossRefPubMed Song ZB, Liu B, Li YY, Wu P, Bao YL, Huang YX, et al. The catalytic triad of testes-specific protease 50 (TSP50) is essential for its function in cell proliferation. Cell Signal. 2014;26:2266–75.CrossRefPubMed
12.
Zurück zum Zitat Li YY, Bao YL, Song ZB, Sun LG, Wu P, Zhang Y, et al. The threonine protease activity of testes-specific protease 50 (TSP50) is essential for its function in cell proliferation. PLoS One. 2012;7, e35030.CrossRefPubMedPubMedCentral Li YY, Bao YL, Song ZB, Sun LG, Wu P, Zhang Y, et al. The threonine protease activity of testes-specific protease 50 (TSP50) is essential for its function in cell proliferation. PLoS One. 2012;7, e35030.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Song ZB, Ni JS, Wu P, Bao YL, Liu T, Li M, et al. Testes-specific protease 50 promotes cell invasion and metastasis by increasing NF-kappaB-dependent matrix metalloproteinase-9 expression. Cell Death Dis. 2015;6, e1703.CrossRefPubMedPubMedCentral Song ZB, Ni JS, Wu P, Bao YL, Liu T, Li M, et al. Testes-specific protease 50 promotes cell invasion and metastasis by increasing NF-kappaB-dependent matrix metalloproteinase-9 expression. Cell Death Dis. 2015;6, e1703.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Mi XG, Song ZB, Wu P, Zhang YW, Sun LG, Bao YL, et al. Alantolactone induces cell apoptosis partially through down-regulation of testes-specific protease 50 expression. Toxicol Lett. 2014;224:349–55.CrossRefPubMed Mi XG, Song ZB, Wu P, Zhang YW, Sun LG, Bao YL, et al. Alantolactone induces cell apoptosis partially through down-regulation of testes-specific protease 50 expression. Toxicol Lett. 2014;224:349–55.CrossRefPubMed
15.
Zurück zum Zitat Pesole G, Grillo G, Larizza A, Liuni S. The untranslated regions of eukaryotic mRNAs: structure, function, evolution and bioinformatic tools for their analysis. Brief Bioinform. 2000;1:236–49.CrossRefPubMed Pesole G, Grillo G, Larizza A, Liuni S. The untranslated regions of eukaryotic mRNAs: structure, function, evolution and bioinformatic tools for their analysis. Brief Bioinform. 2000;1:236–49.CrossRefPubMed
16.
Zurück zum Zitat Wang M, Bao YL, Wu Y, Yu CL, Meng XY, Huang YX, et al. Basic FGF downregulates TSP50 expression via the ERK/Sp1 pathway. J Cell Biochem. 2010;111:75–81.CrossRefPubMed Wang M, Bao YL, Wu Y, Yu CL, Meng XY, Huang YX, et al. Basic FGF downregulates TSP50 expression via the ERK/Sp1 pathway. J Cell Biochem. 2010;111:75–81.CrossRefPubMed
17.
Zurück zum Zitat Kosaka-Suzuki N, Suzuki T, Pugacheva EM, Vostrov AA, Morse 3rd HC, Loukinov D, et al. Transcription factor BORIS (Brother of the Regulator of Imprinted Sites) directly induces expression of a cancer-testis antigen, TSP50, through regulated binding of BORIS to the promoter. J Biol Chem. 2011;286:27378–88.CrossRefPubMedPubMedCentral Kosaka-Suzuki N, Suzuki T, Pugacheva EM, Vostrov AA, Morse 3rd HC, Loukinov D, et al. Transcription factor BORIS (Brother of the Regulator of Imprinted Sites) directly induces expression of a cancer-testis antigen, TSP50, through regulated binding of BORIS to the promoter. J Biol Chem. 2011;286:27378–88.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Wang M, Bao YL, Wu Y, Yu CL, Meng XY, Xu HP, et al. Identification and characterization of the human testes-specific protease 50 gene promoter. DNA Cell Biol. 2008;27:307–14.CrossRefPubMed Wang M, Bao YL, Wu Y, Yu CL, Meng XY, Xu HP, et al. Identification and characterization of the human testes-specific protease 50 gene promoter. DNA Cell Biol. 2008;27:307–14.CrossRefPubMed
19.
Zurück zum Zitat Conne B, Stutz A, Vassalli JD. The 3′ untranslated region of messenger RNA: a molecular ‘hotspot’ for pathology? Nat Med. 2000;6:637–41.CrossRefPubMed Conne B, Stutz A, Vassalli JD. The 3′ untranslated region of messenger RNA: a molecular ‘hotspot’ for pathology? Nat Med. 2000;6:637–41.CrossRefPubMed
20.
Zurück zum Zitat Lopez-Garrido J, Puerta-Fernandez E, Casadesus J. A eukaryotic-like 3′ untranslated region in Salmonella enterica hilD mRNA. Nucleic Acids Res. 2014;42:5894–906.CrossRefPubMedPubMedCentral Lopez-Garrido J, Puerta-Fernandez E, Casadesus J. A eukaryotic-like 3′ untranslated region in Salmonella enterica hilD mRNA. Nucleic Acids Res. 2014;42:5894–906.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Bi X, Zhao Y, Fang W, Yang W. Anticancer activity of Panax notoginseng extract 20(S)-25-OCH3-PPD: targetting beta-catenin signalling. Clin Exp Pharmacol Physiol. 2009;36:1074–8.CrossRefPubMed Bi X, Zhao Y, Fang W, Yang W. Anticancer activity of Panax notoginseng extract 20(S)-25-OCH3-PPD: targetting beta-catenin signalling. Clin Exp Pharmacol Physiol. 2009;36:1074–8.CrossRefPubMed
22.
Zurück zum Zitat Liu Y, Bao YL, Yu CL, Wu Y, Yang XG, Xu HP, et al. Development and characterization of monoclonal antibody specifically against TSP50. Chem Res Chinese U. 2009;25:483–6. Liu Y, Bao YL, Yu CL, Wu Y, Yang XG, Xu HP, et al. Development and characterization of monoclonal antibody specifically against TSP50. Chem Res Chinese U. 2009;25:483–6.
23.
Zurück zum Zitat Shi Y, Bao YL, Wu Y, Yu CL, Huang YX, Sun Y, et al. Alantolactone inhibits cell proliferation by interrupting the interaction between Cripto-1 and activin receptor type II A in activin signaling pathway. J Biomol Screen. 2011;16:525–35.CrossRefPubMed Shi Y, Bao YL, Wu Y, Yu CL, Huang YX, Sun Y, et al. Alantolactone inhibits cell proliferation by interrupting the interaction between Cripto-1 and activin receptor type II A in activin signaling pathway. J Biomol Screen. 2011;16:525–35.CrossRefPubMed
24.
Zurück zum Zitat Yao Y, Zhang YW, Sun LG, Liu BA, Bao YL, Lin H, et al. Juglanthraquinone C, a novel natural compound derived from Juglans mandshurica Maxim, induces S phase arrest and apoptosis in HepG2 cells. Apoptosis. 2012;17:832–41.CrossRefPubMed Yao Y, Zhang YW, Sun LG, Liu BA, Bao YL, Lin H, et al. Juglanthraquinone C, a novel natural compound derived from Juglans mandshurica Maxim, induces S phase arrest and apoptosis in HepG2 cells. Apoptosis. 2012;17:832–41.CrossRefPubMed
25.
Zurück zum Zitat Zheng X, Dai X, Zhao Y, Chen Q, Lu F, Yao D, et al. Restructuring of the dinucleotide-binding fold in an NADP(H) sensor protein. Proc Natl Acad Sci U S A. 2007;104:8809–14.CrossRefPubMedPubMedCentral Zheng X, Dai X, Zhao Y, Chen Q, Lu F, Yao D, et al. Restructuring of the dinucleotide-binding fold in an NADP(H) sensor protein. Proc Natl Acad Sci U S A. 2007;104:8809–14.CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Wang W, Zhang X, Qin JJ, Voruganti S, Nag SA, Wang MH, et al. Natural product ginsenoside 25-OCH3-PPD inhibits breast cancer growth and metastasis through down-regulating MDM2. PLoS One. 2012;7, e41586.CrossRefPubMedPubMedCentral Wang W, Zhang X, Qin JJ, Voruganti S, Nag SA, Wang MH, et al. Natural product ginsenoside 25-OCH3-PPD inhibits breast cancer growth and metastasis through down-regulating MDM2. PLoS One. 2012;7, e41586.CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Kale A, Soylemez F, Ensari A. Expressions of proliferation markers (Ki-67, proliferating cell nuclear antigen, and silver-staining nucleolar organizer regions) and of p53 tumor protein in gestational trophoblastic disease. Am J Obstet Gynecol. 2001;184:567–74.CrossRefPubMed Kale A, Soylemez F, Ensari A. Expressions of proliferation markers (Ki-67, proliferating cell nuclear antigen, and silver-staining nucleolar organizer regions) and of p53 tumor protein in gestational trophoblastic disease. Am J Obstet Gynecol. 2001;184:567–74.CrossRefPubMed
28.
Zurück zum Zitat Yang XG, Bao YL, Huang YX, Sun LG, Zhang YW, Yu CL, et al. 6-[(1-naphthylmethyl)sulfanyl]-9H-purine induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Eur J Pharmacol. 2012;695:27–33.CrossRefPubMed Yang XG, Bao YL, Huang YX, Sun LG, Zhang YW, Yu CL, et al. 6-[(1-naphthylmethyl)sulfanyl]-9H-purine induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Eur J Pharmacol. 2012;695:27–33.CrossRefPubMed
29.
Zurück zum Zitat Chen T, Wong YS. Selenocystine induces S-phase arrest and apoptosis in human breast adenocarcinoma MCF-7 cells by modulating ERK and Akt phosphorylation. J Agric Food Chem. 2008;56:10574–81.CrossRefPubMed Chen T, Wong YS. Selenocystine induces S-phase arrest and apoptosis in human breast adenocarcinoma MCF-7 cells by modulating ERK and Akt phosphorylation. J Agric Food Chem. 2008;56:10574–81.CrossRefPubMed
30.
Zurück zum Zitat Norbury C, Blow J, Nurse P. Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. EMBO J. 1991;10:3321–9.PubMedPubMedCentral Norbury C, Blow J, Nurse P. Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. EMBO J. 1991;10:3321–9.PubMedPubMedCentral
31.
Zurück zum Zitat Li XL, Andersen JB, Ezelle HJ, Wilson GM, Hassel BA. Post-transcriptional regulation of RNase-L expression is mediated by the 3′-untranslated region of its mRNA. J Biol Chem. 2007;282:7950–60.CrossRefPubMed Li XL, Andersen JB, Ezelle HJ, Wilson GM, Hassel BA. Post-transcriptional regulation of RNase-L expression is mediated by the 3′-untranslated region of its mRNA. J Biol Chem. 2007;282:7950–60.CrossRefPubMed
32.
Zurück zum Zitat Gao W, Xiao F, Wang X, Chen T. Artemisinin induces A549 cell apoptosis dominantly via a reactive oxygen species-mediated amplification activation loop among caspase-9, −8 and −3. Apoptosis. 2013;18:1201–13.CrossRefPubMed Gao W, Xiao F, Wang X, Chen T. Artemisinin induces A549 cell apoptosis dominantly via a reactive oxygen species-mediated amplification activation loop among caspase-9, −8 and −3. Apoptosis. 2013;18:1201–13.CrossRefPubMed
33.
Zurück zum Zitat Mondal A, Chatterji U. Artemisinin represses telomerase subunits and induces apoptosis in HPV-39 infected human cervical cancer cells. J Cell Biochem. 2015. Mondal A, Chatterji U. Artemisinin represses telomerase subunits and induces apoptosis in HPV-39 infected human cervical cancer cells. J Cell Biochem. 2015.
34.
Zurück zum Zitat Liu F, Cao Q, Liu N, Li C, You C, Liu C, et al. Overexpression of testes-specific protease 50 (TSP50) predicts poor prognosis in patients with gastric cancer. Gastroenterol Res Pract. 2014;2014:498246.PubMedPubMedCentral Liu F, Cao Q, Liu N, Li C, You C, Liu C, et al. Overexpression of testes-specific protease 50 (TSP50) predicts poor prognosis in patients with gastric cancer. Gastroenterol Res Pract. 2014;2014:498246.PubMedPubMedCentral
35.
Zurück zum Zitat Zheng L, Xie G, Duan G, Yan X, Li Q. High expression of testes-specific protease 50 is associated with poor prognosis in colorectal carcinoma. PLoS One. 2011;6, e22203.CrossRefPubMedPubMedCentral Zheng L, Xie G, Duan G, Yan X, Li Q. High expression of testes-specific protease 50 is associated with poor prognosis in colorectal carcinoma. PLoS One. 2011;6, e22203.CrossRefPubMedPubMedCentral
36.
Zurück zum Zitat Wu YL, Wan Y, Jin XJ, OuYang BQ, Bai T, Zhao YQ, et al. 25-OCH3-PPD induces the apoptosis of activated t-HSC/Cl-6 cells via c-FLIP-mediated NF-kappaB activation. Chem Biol Interact. 2011;194:106–12.CrossRefPubMed Wu YL, Wan Y, Jin XJ, OuYang BQ, Bai T, Zhao YQ, et al. 25-OCH3-PPD induces the apoptosis of activated t-HSC/Cl-6 cells via c-FLIP-mediated NF-kappaB activation. Chem Biol Interact. 2011;194:106–12.CrossRefPubMed
37.
Zurück zum Zitat Eichhorn T, Schloissnig S, Hahn B, Wendler A, Mertens R, Lehmann WD, et al. Bioinformatic and experimental fishing for artemisinin-interacting proteins from human nasopharyngeal cancer cells. Mol Biosyst. 2012;8:1311–8.CrossRefPubMed Eichhorn T, Schloissnig S, Hahn B, Wendler A, Mertens R, Lehmann WD, et al. Bioinformatic and experimental fishing for artemisinin-interacting proteins from human nasopharyngeal cancer cells. Mol Biosyst. 2012;8:1311–8.CrossRefPubMed
Metadaten
Titel
25-methoxyl-dammarane-3β, 12β, 20-triol and artemisinin synergistically inhibit MDA-MB-231 cell proliferation through downregulation of testes-specific protease 50 (TSP50) expression
verfasst von
Danfeng Wang
Yuqing Zhao
Yimeng Wang
Yan Rong
Hongshuang Qin
Yongli Bao
Zhenbo Song
Chunlei Yu
Luguo Sun
Yuxin Li
Publikationsdatum
02.04.2016
Verlag
Springer Netherlands
Erschienen in
Tumor Biology / Ausgabe 9/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-016-5037-7

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