Meklofenamik asit vimentin ifadesini düzenleyerek LNCaP prostat kanseri hücrelerinin invazyon ve migrasyonunu inhibe eder
Öz
Amaç: Prostat kanserinde erken teşhise ve yeni tedavi ajanlarının geliştirilmesine yönelik çeşitli çalışmalara rağmen, tedavide önemli bir ilerleme kaydedilememiştir. Ayrıca, prostat kanserinde metastaz tedavide büyük zorluk oluşturmaktadır. Bu nedenle, bu çalışmada nonsteroid antiinflamatuar bir ilaç olan meclofenamik asidin (MA) LNCaP prostat kanseri hücrelerinin migrasyonu ve invazyonu üzerine etkisinin araştırılması amaçlanmıştır.
Yöntem: İlk olarak, MA'nın LNCaP hücrelerine toksik olmayan konsantrasyonları, tripan mavisi analizi ile belirlendi. Daha sonra, MA'nın migrasyon ve invazyon üzerindeki etkisi, sırasıyla yara iyileştirme analizi ve matrigel invazyon analizi ile değerlendirildi. Son olarak, epitelyal-mezenkimal hücre geçişi için bir belirteç olan vimentinin ifade düzeyi western blotlama ile tespit edildi.
Bulgular: Tripan mavisi analizinin sonuçları, 60 ve 80 µM MA konsantrasyonlarının hücreler için toksik olmadığını göstermiştir. İlaç uygulanmamış kontrol hücrelerinin migrasyon oranı %44,4 iken, bu oran 60 ve 80 µM MA uygulanmış gruplarda istatistiksel olarak önemli ölçüde, sırasıyla, %12,9 ve %2,9'a düşmüştür. 80 µM MA uygulanan hücrelerde invazyon oranının %52'den %30.3'e düştüğü görülmüştür. Western blotlama sonuçları, MA verilen hücrelerde vimentin ifade seviyesinin önemli ölçüde azaldığını göstermiştir.
Sonuç: Çalışma sonucunda, MA'nın vimentin ekspresyon seviyesini azaltarak LNCaP prostat kanseri hücrelerinin migrasyonu ve invazyonunu azalttığı ilk kez gösterilmiştir.
Anahtar Kelimeler
Meklofenamik Asit prostat kanseri invazyon migrasyon vimentin
Kaynakça
- 1. Rawla P. Epidemiology of Prostate Cancer. World J Oncol. Apr 2019;10(2):63-89. doi:10.14740/wjon1191
- 2. Xu S, Zhang Z, Ogawa O, et al. An EP4 antagonist ONO-AE3-208 suppresses cell invasion, migration, and metastasis of prostate cancer. Cell Biochem Biophys. Sep 2014;70(1):521-7. doi:10.1007/s12013-014-9951-2
- 3. De U, Kundu S, Patra N, et al. A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1. Biomol Ther (Seoul). Sep 2015;23(5):434-41. doi:10.4062/biomolther.2015.026
- 4. Jeong JW, Jin CY, Park C, et al. Inhibition of migration and invasion of LNCaP human prostate carcinoma cells by cordycepin through inactivation of Akt. Int J Oncol. May 2012;40(5):1697-704. doi:10.3892/ijo.2012.1332
- 5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. Mar 4 2011;144(5):646-74. doi:10.1016/j.cell.2011.02.013
- 6. Chattopadhyay I, Ambati R, Gundamaraju R. Exploring the Crosstalk between Inflammation and Epithelial-Mesenchymal Transition in Cancer. Mediators Inflamm. 2021;2021:9918379. doi:10.1155/2021/9918379
- 7. Markopoulos GS, Roupakia E, Marcu KB, Kolettas E. Epigenetic Regulation of Inflammatory Cytokine-Induced Epithelial-To-Mesenchymal Cell Transition and Cancer Stem Cell Generation. Cells. Sep 25 2019;8(10)doi:10.3390/cells8101143
- 8. Rayburn ER, Ezell SJ, Zhang R. Anti-Inflammatory Agents for Cancer Therapy. Mol Cell Pharmacol. 2009;1(1):29-43. doi:10.4255/mcpharmacol.09.05
- 9. Delgado-Enciso I, Soriano-Hernandez AD, Rodriguez-Hernandez A, et al. Histological changes caused by meclofenamic acid in androgen-independent prostate cancer tumors: evaluation in a mouse model. Int Braz J Urol. Sep-Oct 2015;41(5):1002-7. doi:10.1590/S1677-5538.IBJU.2013.00186
- 10. Soriano-Hernandez AD, Madrigal-Perez D, Galvan-Salazar HR, et al. Anti-inflammatory drugs and uterine cervical cancer cells: Antineoplastic effect of meclofenamic acid. Oncol Lett. Oct 2015;10(4):2574-2578. doi:10.3892/ol.2015.3580
- 11. Cui Q, Shi H, Ye P, et al. m(6)A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells. Cell Rep. Mar 14 2017;18(11):2622-2634. doi:10.1016/j.celrep.2017.02.059
- 12. Sekine Y, Nakayama H, Miyazawa Y, et al. Simvastatin in combination with meclofenamic acid inhibits the proliferation and migration of human prostate cancer PC-3 cells via an AKR1C3 mechanism. Oncol Lett. Mar 2018;15(3):3167-3172. doi:10.3892/ol.2017.7721
- 13. Wen L, Pan X, Yu Y, Yang B. Down-regulation of FTO promotes proliferation and migration, and protects bladder cancer cells from cisplatin-induced cytotoxicity. BMC Urol. Apr 16 2020;20(1):39. doi:10.1186/s12894-020-00612-7
- 14. Kanli A, Kasap, M., Akpinar, G., Yanar, S. . Changes occurring in the proteome of SH-SY5Y cells caused by fat mass and obesity assocıated (FTO) protein expression reveals multifaceted properties of the FTO protein. . Journal of Health Sciences of Kocaeli University. 2020;6(2):101-112.
- 15. Ahmed S, Alam W, Jeandet P, et al. Therapeutic Potential of Marine Peptides in Prostate Cancer: Mechanistic Insights. Mar Drugs. Jul 22 2022;20(8)doi:10.3390/md20080466
- 16. Siddiqui IA, Malik A, Adhami VM, et al. Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis. Oncogene. Mar 27 2008;27(14):2055-63. doi:10.1038/sj.onc.1210840
- 17. Koshida K, Konaka H, Imao T, Egawa M, Mizokami A, Namiki M. Comparison of two in vivo models for prostate cancer: orthotopic and intratesticular inoculation of LNCaP or PC-3 cells. Int J Urol. Dec 2004;11(12):1114-21. doi:10.1111/j.1442-2042.2004.00961.x
- 18. Koeneman KS, Yeung F, Chung LW. Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate. Jun 1 1999;39(4):246-61. doi:10.1002/(sici)1097-0045(19990601)39:4<246::aid-pros5>3.0.co;2-u
- 19. Chen H, Jia B, Zhang Q, Zhang Y. Meclofenamic Acid Restores Gefinitib Sensitivity by Downregulating Breast Cancer Resistance Protein and Multidrug Resistance Protein 7 via FTO/m6A-Demethylation/c-Myc in Non-Small Cell Lung Cancer. Front Oncol. 2022;12:870636. doi:10.3389/fonc.2022.870636
- 20. Sahinoz B, Kanli, A. Meclofenamic Acid, a Pharmacological Agent, Regulates the m6A Level by Inhibition the FTO Protein in Prostate Cancer Cell Line LNCaP Cells. IKSAD GLOBAL PUBLISHING HOUSE; 2021:195-204.
- 21. Araldi EM, Dell'aica I, Sogno I, Lorusso G, Garbisa S, Albini A. Natural and synthetic agents targeting inflammation and angiogenesis for chemoprevention of prostate cancer. Curr Cancer Drug Targets. Mar 2008;8(2):146-55. doi:10.2174/156800908783769382
- 22. Albini A, Tosetti F, Li VW, Noonan DM, Li WW. Cancer prevention by targeting angiogenesis. Nat Rev Clin Oncol. Sep 2012;9(9):498-509. doi:10.1038/nrclinonc.2012.120
- 23. Moroz A, Delella FK, Almeida R, et al. Finasteride inhibits human prostate cancer cell invasion through MMP2 and MMP9 downregulation. PLoS One. 2013;8(12):e84757. doi:10.1371/journal.pone.0084757
- 24. Lee SH, Hatakeyama S, Yu SY, et al. Core3 O-glycan synthase suppresses tumor formation and metastasis of prostate carcinoma PC3 and LNCaP cells through down-regulation of alpha2beta1 integrin complex. J Biol Chem. Jun 19 2009;284(25):17157-17169. doi:10.1074/jbc.M109.010934
- 25. Shin DY, Lee WS, Jung JH, et al. Flavonoids from Orostachys japonicus A. Berger inhibit the invasion of LnCaP prostate carcinoma cells by inactivating Akt and modulating tight junctions. Int J Mol Sci. Sep 6 2013;14(9):18407-20. doi:10.3390/ijms140918407
- 26. Soriano-Hernandez AD, Galvan-Salazar HR, Montes-Galindo DA, et al. Antitumor effect of meclofenamic acid on human androgen-independent prostate cancer: a preclinical evaluation. Int Urol Nephrol. Apr 2012;44(2):471-7. doi:10.1007/s11255-011-0012-0
- 27. Guzman-Esquivel J, Mendoza-Hernandez MA, Tiburcio-Jimenez D, et al. Decreased biochemical progression in patients with castration-resistant prostate cancer using a novel mefenamic acid anti-inflammatory therapy: A randomized controlled trial. Oncol Lett. Jun 2020;19(6):4151-4160. doi:10.3892/ol.2020.11509
- 28. Kokkinos MI, Wafai R, Wong MK, Newgreen DF, Thompson EW, Waltham M. Vimentin and epithelial-mesenchymal transition in human breast cancer--observations in vitro and in vivo. Cells Tissues Organs. 2007;185(1-3):191-203. doi:10.1159/000101320
- 29. Zhao Y, Yan Q, Long X, Chen X, Wang Y. Vimentin affects the mobility and invasiveness of prostate cancer cells. Cell Biochem Funct. Sep-Oct 2008;26(5):571-7. doi:10.1002/cbf.1478
- 30. Lang SH, Hyde C, Reid IN, et al. Enhanced expression of vimentin in motile prostate cell lines and in poorly differentiated and metastatic prostate carcinoma. Prostate. Sep 1 2002;52(4):253-63. doi:10.1002/pros.10088
Meclofenamic acid inhibits the invasion and migration of LNCaP prostate carcinoma cells by regulating vimentin expression
Öz
Objectives: Despite various studies to improve the early detection and development of novel treatment agents, no significant progress has been made in the treatment of prostate cancer. Moreover, the metastasis of prostate carcinoma is a major challenge in treatment modalities. Therefore, in the present study, it was aimed to investigate the effect of meclofenamic acid (MA), a nonsteroidal anti-inflammatory drug, on the migration and invasion of LNCaP prostate carcinoma cells.
Methods: Firstly, the non-toxic concentrations of MA on LNCaP cells were determined by trypan blue exclusion assay. After that, the effect of MA on migration and invasion was assessed by wound healing assay and matrigel invasion assay, respectively. Finally, the expression level of vimentin, which is a marker for epithelial-to-mesenchymal cell transition, was assessed by western blotting.
Results: The results of trypan blue exclusion assay showed that 60 and 80 µM concentrations of MA were non-toxic to the cells. The migration rate of non-treated control cells was 44.4%, while it was significantly reduced to 12.9% and 2.9% in 60 and 80 µM MA-treated groups, respectively. When the cells were treated with 80 µM MA, the drug significantly reduced the invasion of LNCaP cells from 52% to 30.3%. Western blot results showed that the level of vimentin expression was significantly decreased in MA-treated cells.
Conclusion: The study shows for the first time that MA inhibits the invasion and migration of prostate cancer LNCaP cells by decreasing the expression level of vimentin.
Anahtar Kelimeler
Meclofenamic acid prostate cancer invasion migration vimentin
Kaynakça
- 1. Rawla P. Epidemiology of Prostate Cancer. World J Oncol. Apr 2019;10(2):63-89. doi:10.14740/wjon1191
- 2. Xu S, Zhang Z, Ogawa O, et al. An EP4 antagonist ONO-AE3-208 suppresses cell invasion, migration, and metastasis of prostate cancer. Cell Biochem Biophys. Sep 2014;70(1):521-7. doi:10.1007/s12013-014-9951-2
- 3. De U, Kundu S, Patra N, et al. A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1. Biomol Ther (Seoul). Sep 2015;23(5):434-41. doi:10.4062/biomolther.2015.026
- 4. Jeong JW, Jin CY, Park C, et al. Inhibition of migration and invasion of LNCaP human prostate carcinoma cells by cordycepin through inactivation of Akt. Int J Oncol. May 2012;40(5):1697-704. doi:10.3892/ijo.2012.1332
- 5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. Mar 4 2011;144(5):646-74. doi:10.1016/j.cell.2011.02.013
- 6. Chattopadhyay I, Ambati R, Gundamaraju R. Exploring the Crosstalk between Inflammation and Epithelial-Mesenchymal Transition in Cancer. Mediators Inflamm. 2021;2021:9918379. doi:10.1155/2021/9918379
- 7. Markopoulos GS, Roupakia E, Marcu KB, Kolettas E. Epigenetic Regulation of Inflammatory Cytokine-Induced Epithelial-To-Mesenchymal Cell Transition and Cancer Stem Cell Generation. Cells. Sep 25 2019;8(10)doi:10.3390/cells8101143
- 8. Rayburn ER, Ezell SJ, Zhang R. Anti-Inflammatory Agents for Cancer Therapy. Mol Cell Pharmacol. 2009;1(1):29-43. doi:10.4255/mcpharmacol.09.05
- 9. Delgado-Enciso I, Soriano-Hernandez AD, Rodriguez-Hernandez A, et al. Histological changes caused by meclofenamic acid in androgen-independent prostate cancer tumors: evaluation in a mouse model. Int Braz J Urol. Sep-Oct 2015;41(5):1002-7. doi:10.1590/S1677-5538.IBJU.2013.00186
- 10. Soriano-Hernandez AD, Madrigal-Perez D, Galvan-Salazar HR, et al. Anti-inflammatory drugs and uterine cervical cancer cells: Antineoplastic effect of meclofenamic acid. Oncol Lett. Oct 2015;10(4):2574-2578. doi:10.3892/ol.2015.3580
- 11. Cui Q, Shi H, Ye P, et al. m(6)A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells. Cell Rep. Mar 14 2017;18(11):2622-2634. doi:10.1016/j.celrep.2017.02.059
- 12. Sekine Y, Nakayama H, Miyazawa Y, et al. Simvastatin in combination with meclofenamic acid inhibits the proliferation and migration of human prostate cancer PC-3 cells via an AKR1C3 mechanism. Oncol Lett. Mar 2018;15(3):3167-3172. doi:10.3892/ol.2017.7721
- 13. Wen L, Pan X, Yu Y, Yang B. Down-regulation of FTO promotes proliferation and migration, and protects bladder cancer cells from cisplatin-induced cytotoxicity. BMC Urol. Apr 16 2020;20(1):39. doi:10.1186/s12894-020-00612-7
- 14. Kanli A, Kasap, M., Akpinar, G., Yanar, S. . Changes occurring in the proteome of SH-SY5Y cells caused by fat mass and obesity assocıated (FTO) protein expression reveals multifaceted properties of the FTO protein. . Journal of Health Sciences of Kocaeli University. 2020;6(2):101-112.
- 15. Ahmed S, Alam W, Jeandet P, et al. Therapeutic Potential of Marine Peptides in Prostate Cancer: Mechanistic Insights. Mar Drugs. Jul 22 2022;20(8)doi:10.3390/md20080466
- 16. Siddiqui IA, Malik A, Adhami VM, et al. Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis. Oncogene. Mar 27 2008;27(14):2055-63. doi:10.1038/sj.onc.1210840
- 17. Koshida K, Konaka H, Imao T, Egawa M, Mizokami A, Namiki M. Comparison of two in vivo models for prostate cancer: orthotopic and intratesticular inoculation of LNCaP or PC-3 cells. Int J Urol. Dec 2004;11(12):1114-21. doi:10.1111/j.1442-2042.2004.00961.x
- 18. Koeneman KS, Yeung F, Chung LW. Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate. Jun 1 1999;39(4):246-61. doi:10.1002/(sici)1097-0045(19990601)39:4<246::aid-pros5>3.0.co;2-u
- 19. Chen H, Jia B, Zhang Q, Zhang Y. Meclofenamic Acid Restores Gefinitib Sensitivity by Downregulating Breast Cancer Resistance Protein and Multidrug Resistance Protein 7 via FTO/m6A-Demethylation/c-Myc in Non-Small Cell Lung Cancer. Front Oncol. 2022;12:870636. doi:10.3389/fonc.2022.870636
- 20. Sahinoz B, Kanli, A. Meclofenamic Acid, a Pharmacological Agent, Regulates the m6A Level by Inhibition the FTO Protein in Prostate Cancer Cell Line LNCaP Cells. IKSAD GLOBAL PUBLISHING HOUSE; 2021:195-204.
- 21. Araldi EM, Dell'aica I, Sogno I, Lorusso G, Garbisa S, Albini A. Natural and synthetic agents targeting inflammation and angiogenesis for chemoprevention of prostate cancer. Curr Cancer Drug Targets. Mar 2008;8(2):146-55. doi:10.2174/156800908783769382
- 22. Albini A, Tosetti F, Li VW, Noonan DM, Li WW. Cancer prevention by targeting angiogenesis. Nat Rev Clin Oncol. Sep 2012;9(9):498-509. doi:10.1038/nrclinonc.2012.120
- 23. Moroz A, Delella FK, Almeida R, et al. Finasteride inhibits human prostate cancer cell invasion through MMP2 and MMP9 downregulation. PLoS One. 2013;8(12):e84757. doi:10.1371/journal.pone.0084757
- 24. Lee SH, Hatakeyama S, Yu SY, et al. Core3 O-glycan synthase suppresses tumor formation and metastasis of prostate carcinoma PC3 and LNCaP cells through down-regulation of alpha2beta1 integrin complex. J Biol Chem. Jun 19 2009;284(25):17157-17169. doi:10.1074/jbc.M109.010934
- 25. Shin DY, Lee WS, Jung JH, et al. Flavonoids from Orostachys japonicus A. Berger inhibit the invasion of LnCaP prostate carcinoma cells by inactivating Akt and modulating tight junctions. Int J Mol Sci. Sep 6 2013;14(9):18407-20. doi:10.3390/ijms140918407
- 26. Soriano-Hernandez AD, Galvan-Salazar HR, Montes-Galindo DA, et al. Antitumor effect of meclofenamic acid on human androgen-independent prostate cancer: a preclinical evaluation. Int Urol Nephrol. Apr 2012;44(2):471-7. doi:10.1007/s11255-011-0012-0
- 27. Guzman-Esquivel J, Mendoza-Hernandez MA, Tiburcio-Jimenez D, et al. Decreased biochemical progression in patients with castration-resistant prostate cancer using a novel mefenamic acid anti-inflammatory therapy: A randomized controlled trial. Oncol Lett. Jun 2020;19(6):4151-4160. doi:10.3892/ol.2020.11509
- 28. Kokkinos MI, Wafai R, Wong MK, Newgreen DF, Thompson EW, Waltham M. Vimentin and epithelial-mesenchymal transition in human breast cancer--observations in vitro and in vivo. Cells Tissues Organs. 2007;185(1-3):191-203. doi:10.1159/000101320
- 29. Zhao Y, Yan Q, Long X, Chen X, Wang Y. Vimentin affects the mobility and invasiveness of prostate cancer cells. Cell Biochem Funct. Sep-Oct 2008;26(5):571-7. doi:10.1002/cbf.1478
- 30. Lang SH, Hyde C, Reid IN, et al. Enhanced expression of vimentin in motile prostate cell lines and in poorly differentiated and metastatic prostate carcinoma. Prostate. Sep 1 2002;52(4):253-63. doi:10.1002/pros.10088
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Biyokimya ve Hücre Biyolojisi (Diğer), Klinik Tıp Bilimleri |
| Bölüm | Araştırma Makaleleri |
| Yazarlar | |
| Yayımlanma Tarihi | 15 Ekim 2022 |
| Gönderilme Tarihi | 25 Ağustos 2022 |
| Kabul Tarihi | 13 Eylül 2022 |
| Yayımlandığı Sayı | Yıl 2022 Cilt: 5 Sayı: 3 |
"Acta Medica Nicomedia" Tıp dergisinde https://dergipark.org.tr/tr/pub/actamednicomedia adresinden yayımlanan makaleler açık erişime sahip olup Creative Commons Atıf-AynıLisanslaPaylaş 4.0 Uluslararası Lisansı (CC BY SA 4.0) ile lisanslanmıştır.