Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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A curcumin analog CA-5f inhibits urokinase-type plasminogen activator and invasive phenotype of triple-negative breast cancer cells

  • Kim, Minjoo (Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University) ;
  • Moon, Aree (Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University)
  • Received : 2021.09.25
  • Accepted : 2021.10.18
  • Published : 2022.01.15
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Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive types of breast cancer with poor outcomes. Patients with TNBC cannot beneft from targeted therapies such as Tamoxifen and Herceptin. The aim of the present study was to seek a preventive or therapeutic agent with a potential inhibitory efect on aggressive progression of TNBC. Anticancer efect of a natural compound curcumin have been demonstrated, however, development of more efective curcumin analogs with better bioavailability is needed. We investigated if a curcumin analog CA-5f could inhibit the invasive phenotype of TNBC cell lines in the present study. Treatment with CA-5f inhibited the viability of MDA-MB-231 and Hs578T TNBC cells, possible by inducing apoptosis. The invasive phenotypes of these cells were inhibited by CA-5f in a concentration-dependent manner. Protein expression of urokinase-type plasminogen activator (uPA), a serine protease known to degrade the extracellular matrix and lead to invasion, was markedly decreased by CA-5f in Hs578T cells. However, mRNA level of uPA was not altered by CA-5f, implicating that the efect of CA-5f was not through transcriptional regulation. Of note, CA-5f upregulated plasminogen activator inhibitor type (PAI)-1, which is known to inhibit uPA by interacting with urokinase-type plasminogen receptor, in TNBC cells. Taken together, these results demonstrated that CA-5f signifcantly inhibited the invasive phenotype of TNBC cells, possibly by decreasing the protein level of uPA through upregulating PAI-1. Our results may provide useful information on developing CA-5f as a potential therapeutic agent against malignant progression of TNBC.

Keywords

Acknowledgement

This Research was supported by Duksung Women's University Research Grant 2019. The authors thank Dr. Hao Jin (Duksung Innovative Drug Center) for helpful discussion.

References

  1. Curado MP (2011) Breast cancer in the world: Incidence and mortality. Salud Publica de Mex 53:372-384. https://www.medigraphic.com/cgi-bin/new/resumenI.cgi?IDREVISTA=79&IDARTICULO=31619&IDPUBLICACION=3422
  2. Redig AJ, McAllister SS (2013) Breast cancer as a systemic disease: a view of metastasis. J Intern Med 274:113-126. https://doi.org/10.1111/joim.12084
  3. Nakhjavani M, Hardingham JE, Palethorpe HM, Price TJ, Townsend AR (2019) Druggable molecular targets for the treatment of triple negative breast cancer. J Breast Cancer 22:341-361. https://doi.org/10.4048/jbc.2019.22.e39
  4. Shi M, Liu D, Duan H, Shen B, Guo N (2010) Metastasis-related miRNAs, active players in breast cancer invasion, and metastasis. Cancer Metastasis Rev 29:785-799. https://doi.org/10.1007/s10555-010-9265-9
  5. Cleere DW (2010) Triple-negative breast cancer: a clinical update. Community Oncol 7:203-211. https://doi.org/10.1016/s1548-5315(11)70394-1
  6. Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA (1993) Molecular aspects of tumor cell invasion and metastasis. Cancer 71:1368-1383. https://doi.org/10.1002/1097-0142(19930215)71:4%3c1368::aid-cncr2820710432%3e3.0.co;2-l
  7. Liotta LA, Trygguason K, Garbisa S, Hart I, Foltz CM, Shafe S (1980) Metastasis potential correlate with enzymatic degradation of basement membrane collagen. Nature 284:67-68. https://doi.org/10.1038/284067a0
  8. Stamenkovic I (2000) Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol 10:415-433. https://doi.org/10.1006/scbi.2000.0379
  9. Brungs D, Chen J, Aghmesheh M, Vine KL, Becker TM, Carolan MG, Ranson M (2017) The urokinase plasminogen activation system in gastroesophageal cancer: a systematic review and meta-analysis. Oncotarget 8:23099-23109. https://doi.org/10.18632/oncotarget.15485
  10. Lijnen HR (2002) Matrix metalloproteinases and cellular fbrinolytic activity. Biochem. (Moscow) 67:92-98. https://doi.org/10.1023/a:1013908332232
  11. Wilkins-Port CE, Higgins SP, Higgins CE, Kobori-Hotchkiss I, Higgins PJ (2012) Complex regulation of the pericellular proteolytic microenvironment during tumor progression and wound repair: functional interactions between the serine protease and matrix metalloproteinase cascades. Biochem Res Int 2012:454368. https://doi.org/10.1155/2012/454368
  12. Ulisse S, Baldini E, Bocchini S, D'Armiento M (2008) The encyclopedia of cancer. In: Schwab M (ed) Plasminogen activating system, 2009th edn. Springer, Berlin, Heidelberg, New York, pp 134-137
  13. Jannicke F, Schmitt M, Pache L, Ulm K, Harbeck N, Hofer H, Graef H (1993) Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 24:195-208. https://doi.org/10.1007/bf01833260
  14. Praus M, Collen D, Gerard RD (2002) Both u-PA inhibition and vitronectin binding by plasminogen activator inhibitor 1 regulate HT1080 fbrosarcoma cell metastasis. Inl J Cancer 102:584-591. https://doi.org/10.1002/ijc.10767
  15. Lin SR, Fu YS, Tsai MJ, Cheng H, Weng CF (2017) Natural compounds from herbs that can potentially execute as autophagy inducers for cancer therapy. Int J Mol Sci 18:1412. https://doi.org/10.3390/ijms18071412
  16. Kunnumakkara AB, Anand P, Aggarwal BB (2008) Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of diferent cancers through interaction with multiple cell signaling proteins. Cancer Lett 269:199-225. https://doi.org/10.1016/j.canlet.2008.03.009
  17. Kim MS, Kang HJ, Moon A (2001) Inhibition of invasion and induction of apoptosis by curcumin in H-ras-transformed MCF10A human breast epithelial cells. Arch Pharm Res 24:349-354. https://doi.org/10.1007/bf02975105
  18. Zhou X, Jiao D, Dou M, Zhang W et al (2020) Curcumin inhibits the growth of triple-negative breast cancer cells by silencing EZH2 and restoring DLC1 expression. J Cell Mol Med 24:10648-10662. https://doi.org/10.1111/jcmm.15683
  19. Shindikar A, Singh A, Nobre M, Kirolikar S (2016) Curcumin and resveratrol as promising natural remedies with nanomedicine approach for the efective treatment of triple negative breast cancer. J Oncol 2016:9750785. https://doi.org/10.1155/2016/9750785
  20. Adams BK, Cai J, Armstrong J, Herold M et al (2005) EF24, a novel synthetic curcumin analog, induces apoptosisin cancer cells via a redox-dependent mechanism. Anticancer Drugs 16:263-275. https://doi.org/10.1097/00001813-200503000-00005
  21. Zhang L, Qiang P, Yu J, Miao Y et al (2019) Identifcation of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor efect against non-small cell lung cancer. Autophagy 15:391-406. https://doi.org/10.1080/15548627.2018.1511503
  22. Guan F, Ding Y, Zhang Y, Zhou Y, Li M, Wang C (2016) Curcumin suppresses proliferation and migration of MDA-MB-231breast cancer cells through autophagy-dependent Akt degradation. PLoS ONE 11:e0146553. https://doi.org/10.1371/journal.pone.0146553
  23. Wang K, Zhang C, Bao J, Jia X et al (2016) Synergistic chemopreventive efects of curcumin and berberine on human breast cancer cells through induction of apoptosis and autophagic cell death. Sci Rep 6:26064. https://doi.org/10.1038/srep26064
  24. Jiang P, Mizushima N (2014) Autophagy and human diseases. Cell Res 24:69-79. https://doi.org/10.1038/cr.2013.161
  25. Lefort S et al (2014) Inhibition of autophagy as a new means of improving chemotherapy efciency in high-LC3B triple-negative breast cancers. Autophagy 10:2122-2142. https://doi.org/10.4161/15548627.2014.981788
  26. Wang MC et al (2015) Autophagic regulation of cell growth by altered expression of Beclin 1 in triple-negative breast cancer. Int J Clin Exp Med 8:7049-7058 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509187/
  27. Shin I, Kim S, Song H, Kim HRC, Moon A (2005) H-Ras-specifc activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. J Biol Chem 280:14675-14683. https://doi.org/10.1074/jbc.m411625200
  28. Koh M, Woo Y, Valiathan RR, Jung HY et al (2015) Discoidin domain receptor 1 is a novel transcriptional target of ZEB1 in breast epithelial cells undergoing H-Ras-induced epithelial to mesenchymal transition. Int J Cancer 136:E508-E520. https://doi.org/10.1002/ijc.29154
  29. Boulares AH, Yakovlev AG, Ivanova V, Stoica BA et al (1999) Role of poly (ADP-ribose) polymerase (PARP) cleavage in apoptosis: caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. J Biol Chem 274:22932-22940. https://doi.org/10.1074/jbc.274.33.22932
  30. Jin H, Choi H, Kim ES, Lee HH, Cho H, Moon A (2021) Natural killer cells inhibit breast cancer cell invasion through down-regulation of urokinase-type plasminogen activator. Oncol Rep 45:299-308. https://doi.org/10.3892/or.2020.7840
  31. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srivinas PS (1998) Infuence ofpiperine on the in animals pharmacokinetics of curcumin and humanvolunteers. Planta Med 64:353-356. https://doi.org/10.1055/s-2006-957450
  32. Jitariu AA, Cimpean AM, Ribatti D, Raica M (2017) Triple negative breast cancer: the kiss of death. Oncotarget 8:46652-46662. https://doi.org/10.18632/oncotarget.16938
  33. Sotiriou C, Neo SY, McShane LM, Korn EL et al (2003) Breast cancer classifcation and prognosis based on gene expression profles from a population-based study. PNAS 100:10393-10398. https://doi.org/10.1073/pnas.1732912100
  34. Kaplan HG, Malmgren JA (2008) Impact of triple negative phenotype on breast cancer prognosis. Breast J 14:456-463. https://doi.org/10.1111/j.1524-4741.2008.00622.x
  35. Stetler-Stenvenson WG (1990) Type IV collagenase in tumor invasion and metastasis. Cancer Metastasis Rev 9:289-303. https://doi.org/10.1007/BF00049520
  36. Holst-Hansen C, Johannessen B, Hoyer-Hansen G, Romer J, Ellis V, Brunner N (1996) Urokinase-type plasminogen activation in three human breast cancer cell lines correlates with their in vitro invasiveness. Clin Exp Metastasis 14:297-307. https://doi.org/10.1007/BF00053903
  37. Mauro CD, Pesapane A, Formisano L, Rosa R et al (2017) Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors. Sci Rep 7:9388. https://doi.org/10.1038/s41598-017-10062-1
  38. Mahmood N, Mihalcioiu C, Rabbani SA (2018) Multifaceted role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): Diagnostic, prognostic, and therapeutic applications. Front Oncol 8:24. https://doi.org/10.3389/fonc.2018.00024
  39. Wang L, Madigan MC, Chen H, Liu F et al (2009) Expression of urokinase plasminogen activator and its receptor in advanced epithelial ovarian cancer patients. Gynecol Oncol 114:265-272. https://doi.org/10.1016/j.ygyno.2009.04.031
  40. Han B, Nakamura M, Zhou G, Ishii A, Nakamura A, Bai Y, Mori I, Kakudo K (2006) Calcitonin inhibits invasion of breast cancer cells: Involvement of urokinase-type plasminogen activator (uPA) and uPA receptor. Int J Oncol 28:807-814. https://doi.org/10.3892/ijo.28.4.807
  41. Guo Y, Pakneshan P, Gladu J, Slack A, Szyf M, Rabbani SA (2002) Regulation of DNA methylation in human breast cancer: efect on the urokinase-type plasminogen activator gene production and tumor invasion. J Biol Chem 277:41571-41579. https://doi.org/10.1074/jbc.M201864200
  42. Rau JC, Beaulieu LM, Huntington JA, Church FC (2007) Serpins in thrombosis, hemostasis and fbrinolysis. J Thromb Haemost 5:102-115. https://doi.org/10.1111/j.1538-7836.2007.02516.x
  43. Paramita P, Wardhani BW, Wanandi SI, Louisa M (2018) Curcumin for the prevention of ephithelial-mesenchymal transition in endoxifen-treated MCF-7 breast cancer cells. Asian Pac J Cancer Prev 19:1243-1249. https://doi.org/10.22034/APJCP.2018.19.5.1243
  44. Eddy AA, Fogo AB (2006) Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of action. JASN 17:2999-3012. https://doi.org/10.1681/ASN.2006050503
  45. Sof GA, Sanderowitz J, Gately S, Verrusio E, Weiss I, Brem S, Kwaan HC (1996) Expression of plasminogen activator inhibitor type 1 in human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in athymic mouse model. J Clin Invest 96:2593-2600. https://doi.org/10.1172/JCI118323
  46. Schmitt M, Harbeck N, Thomssen C, Wilhelm O, Magdolen V, Reuning U, Ulm K, Hofer H, Janicke F, Graef H (1997) Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. Thromb 78:285-296. https://doi.org/10.1055/s-0038-1657541