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Auranofin Suppresses Plasminogen Activator Inhibitor-2 Expression through Annexin A5 Induction in Human Prostate Cancer Cells  

Shin, Dong-Won (College of Pharmacy, Chung-Ang University)
Kwon, Yeo-Jung (College of Pharmacy, Chung-Ang University)
Ye, Dong-Jin (College of Pharmacy, Chung-Ang University)
Baek, Hyoung-Seok (College of Pharmacy, Chung-Ang University)
Lee, Joo-Eun (College of Pharmacy, Chung-Ang University)
Chun, Young-Jin (College of Pharmacy, Chung-Ang University)
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Biomolecules & Therapeutics / v.25, no.2, 2017 , pp. 177-185 More about this Journal
Auranofin has been developed as antirheumatic drugs, which is currently under clinical development for the treatment of chronic lymphocytic leukemia. Previous report showed that auranofin induced apoptosis by enhancement of annexin A5 expression in PC-3 cells. To understand the role of annexin A5 in auranofin-mediated apoptosis, we performed microarray data analysis to study annexin A5-controlled gene expression in annexin A5 knockdown PC-3 cells. Of differentially expressed genes, plasminogen activator inhibitor (PAI)-2 was increased by annexin A5 siRNA confirmed by qRT-PCR and western blot. Treatment with auranofin decreased PAI-2 and increased annexin A5 expression as well as promoting apoptosis. Furthermore, auranofin-induced apoptosis was recovered by annexin A5 siRNA but it was promoted by PAI-2 siRNA. Interestingly, knockdown of annexin A5 rescued PAI-2 expression suppressed by auranofin. Taken together, our study suggests that induction of annexin A5 by auranofin may enhance apoptosis through suppression of PAI-2 expression in PC-3 cells.
Annexin A5; Apoptosis; Auranofin; Plasminogen activator inhibitor-2;
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1 Liu, N., Li, X., Huang, H., Zhao, C., Liao, S., Yang, C., Liu, S., Song, W., Lu, X., Lan, X., Chen, X., Yi, S., Xu, L., Jiang, L., Zhao, C., Dong, X., Zhou, P., Li, S., Wang, S., Shi, X., Dou, P. Q., Wang, X. and Liu, J. (2014) Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth. Oncotarget 5, 5453-5471.   DOI
2 Boersma, H. H., Kietselaer, B. L., Stolk, L. M., Bennaghmouch, A., Hofstra, L., Narula, J., Heidendal, G. A. and Reutelingsperger, C. P. (2005) Past, present, and future of annexin A5: from protein discovery to clinical applications. J. Nucl. Med. 46, 2035-2050.
3 Bohn, H. and Kraus, W. (1979) Isolation and characterization of a new placenta specific protein (PP10) (author's transl). Arch. Gynecol. 227, 125-134.   DOI
4 Bolstad, B. M., Irizarry, R. A., Astrand, M. and Speed, T. P. (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185-193.   DOI
5 Cardo-Vila, M., Arap, W. and Pasqualini, R. (2003) ${\alpha}v{\beta}5$ integrin-dependent programmed cell death triggered by a peptide mimic of annexin V. Mol. Cell 11, 1151-1162.   DOI
6 (2016) Phase I and II study of auranofin in chronic lymphocytic leukemia (CLL). Available from:
7 Croucher, D. R., Saunders, D. N., Lobov, S. and Ranson, M. (2008) Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat. Rev. Cancer 8, 535-545.   DOI
8 Demange, P., Voges, D., Benz, J., Liemann, S., Göttig, P., Berendes, R., Burger, A. and Huber, R. (1994) Annexin V: the key to understanding ion selectivity and voltage regulation? Trends Biochem. Sci. 19, 272-276.   DOI
9 Mahoney, C. W., Hensey, C. E. and Azzi, A. (1989) Auranofin, gold thiomalate, and gold thioglucose inhibit protein kinase C. Biochem. Pharmacol. 38, 3383-3386.   DOI
10 Marzano, C., Gandin, V., Folda, A., Scutari, G., Bindoli, A. and Rigobello, M. P. (2007) Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells. Free Radic. Biol. Med. 42, 872-881.   DOI
11 Medcalf, R. L. and Stasinopoulos, S. J. (2005) The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. FEBS J. 272, 4858-4867.   DOI
12 Nakaya, A., Sagawa, M., Muto, A., Uchida, H., Ikeda, Y. and Kizaki, M. (2011) The gold compound auranofin induces apoptosis of human multiple myeloma cells through both down-regulation of STAT3 and inhibition of NF-${\kappa}B$ activity. Leuk. Res. 35, 243-249.   DOI
13 Nordengren, J., Fredstorp Lidebring, M., Bendahl, P. O., Brunner, N., Fernö, M., Hogberg, T., Stephens, R. W., Wilen, R. and Casslen, B. (2002) High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI-2) is an independent marker for shorter progression-free survival in patients with early stage endometrial cancer. Int. J. Cancer 97, 379-385.   DOI
14 Park, N. and Chun, Y. J. (2014) Auranofin promotes mitochondrial apoptosis by inducing annexin A5 expression and translocation in human prostate cancer cells. J. Toxicol. Environ. Health Part A 77, 1467-1476.   DOI
15 Irizarry, R. A., Hobbs, B., Collin, F., Beazer-Barclay, Y. D., Antonellis, K. J., Scherf, U. and Speed, T. P. (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249-264.   DOI
16 Dickinson, J. L., Bates, E. J., Ferrante, A. and Antalis, T. M. (1995) Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor ${\alpha}$-induced apoptosis. J. Biol. Chem. 270, 27894-27904.   DOI
17 Eisen, M. B., Spellman, P. T., Brown, P. O. and Botstein, D. (1998) Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. U.S.A. 95, 14863-14868.   DOI
18 Ganesh, S., Sier, C. F., Griffioen, G., Vloedgraven, H. J., de Boer, A., Welvaart, K., van de Velde, C. J., van Krieken, J. H., Verheijen, J. H., Lamers, C. B. H. W. and Verspaget, H. W. (1994) Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res. 54, 4065-4071.
19 Han, S., Kim, K., Kim, H., Kwon, J., Lee, Y. H., Lee, C. K., Song, Y., Lee, S. J., Ha, N. and Kim, K. (2008) Auranofin inhibits overproduction of pro-inflammatory cytokines, cyclooxygenase expression and PGE2 production in macrophages. Arch. Pharm. Res. 31, 67-74.   DOI
20 Hong, M., Park, N. and Chun, Y. J. (2014) Role of annexin a5 on mitochondria-dependent apoptosis induced by tetramethoxystilbene in human breast cancer cells. Biomol. Ther. (Seoul) 22, 519-524.   DOI
21 Stern, I., Wataha, J. C., Lewis, J. B., Messer, R. L. W., Lockwood, P. E. and Tseng, W. Y. (2005) Anti-rheumatic gold compounds as sublethal modulators of monocytic LPS-induced cytokine secretion. Toxicol. In Vitro 19, 365-371.   DOI
22 Park, S. H., Lee, J. H., Berek, J. S. and Hu, M. C. (2014) Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. Int. J. Oncol. 45, 1691-1698.   DOI
23 Irving, J. A., Pike, R. N., Lesk, A. M. and Whisstock, J. C. (2000) Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function. Genome Res. 10, 1845-1864.   DOI
24 Jeon, K. I., Jeong, J. Y. and Jue, D. M. (2000) Thiol-reactive metal compounds inhibit NF-${\kappa}B$ activation by blocking $I{\kappa}B$ kinase. J. Immunol. 164, 5981-5989.   DOI
25 Jeong, J. J., Park, N., Kwon, Y. J., Ye, D. J., Moon, A. and Chun, Y. J. (2014) Role of annexin A5 in cisplatin-induced toxicity in renal cells: molecular mechanism of apoptosis. J. Biol. Chem. 289, 2469-2481.   DOI
26 Reutelingsperger, C. P., Hornstra, G. and Hemker, H. C. (1985) Isolation and partial purification of a novel anticoagulant from arteries of human umbilical cord. Eur. J. Biochem. 151, 625-629.   DOI
27 Rothhut, B., Dubois, T., Feliers, D., Russo-Marie, F. and Oudinet, J. P. (1995) Inhibitory effect of annexin V on protein kinase C activity in mesangial cell lysates. Eur. J. Biochem. 232, 865-872.   DOI
28 Silverman, G. A., Jockel, J. I., Domer, P. H., Mohr, R. M., Taillon-Miller, P. and Korsmeyer, S. J. (1991) Yeast artificial chromosome cloning of a two-megabase-size contig within chromosomal band 18q21 establishes physical linkage between BCL2 and plasminogen activator inhibitor type-2. Genomics 9, 219-228.   DOI
29 Stringer, B., Udofa, E. A. and Antalis, T. M. (2012) Regulation of the human plasminogen activator inhibitor type 2 gene: cooperation of an upstream silencer and transactivator. J. Biol. Chem. 287, 10579-10589.   DOI
30 Vermes, I., Haanen, C., Steffens-Nakken, H. and Reutelingsperger, C. (1995) A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J. Immunol. Methods 184, 39-51.   DOI
31 Zhou, H. M., Bolon, I., Nichols, A., Wohlwend, A. and Vassalli, J. D. (2001) Overexpression of plasminogen activator inhibitor type 2 in basal keratinocytes enhances papilloma formation in transgenic mice. Cancer Res. 61, 970-976.
32 Koopman, G., Reutelingsperger, C. P., Kuijten, G. A., Keehnen, R. M., Pals, S. T. and van Oers, M. H. (1994) Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84, 1415-1420.
33 Jing, J., Chen, L., Fu, H. Y., Fan, K., Yao, Q., Ge Y. F., Lu, J. C. and Yao, B. (2015) Annexin V-induced rat Leydig cell proliferation involves Ect2 via RhoA/ROCK signaling pathway. Sci. Rep. 5, 9437.   DOI
34 Kean, W. F., Hart, L. and Buchanan, W. W. (1997) Auranofin. Br. J. Rheumatol. 36, 560-572.   DOI
35 Kim, N. H., Lee, M. Y., Park, S. J., Choi, J. S., Oh, M. K. and Kim, I. S. (2007) Auranofin blocks interleukin-6 signalling by inhibiting phosphorylation of JAK1 and STAT3. Immunology 122, 607-614.   DOI
36 Kruithof, E. K., Baker, M. S. and Bunn, C. L. (1995) Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 86, 4007-4024.
37 Li, H., Hu, J., Wu, S., Wang, L., Cao, X., Zhang, X., Dai, B., Cao, M., Shao, R., Zhang, R., Majidi, M., Ji, L., Heymach, J. V., Wang, M., Pan, S., Minna, J., Mehran, R. J., Swisher, S. G., Roth, J. A. and Fang, B. (2016) Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells. Oncotarget 7, 3548-3558.   DOI
38 Kumar, S. and Baglioni, C. (1991) Protection from tumor necrosis factor-mediated cytolysis by overexpression of plasminogen activator inhibitor type-2. J. Biol. Chem. 266, 20960-20964.
39 Kwon, Y. J., Jung, J. J., Park, N. H., Ye, D. J., Kim, D., Moon, A. and Chun, Y. J. (2013) Annexin A5 as a new potential biomarker for cisplatin-induced toxicity in human kidney epithelial cells. Biomol. Ther. (Seoul) 21, 190-195.   DOI