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Anti-Cancer Agents in Medicinal Chemistry

Author(s): Sercan Ergün*, Oğuzhan Akgün, Neslihan Taşkurt Hekim, Senanur Aslan, Ferda Ari, Sezgin Güneş and Ümmet Abur

DOI: 10.2174/1871520622666220601093452

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The Interrelationship Between FYN and miR-128/193a-5p/494 in Imatinib Resistance in Prostate Cancer

Page: [360 - 365] Pages: 6

  • * (Excluding Mailing and Handling)

Abstract

Background: C-KIT is a receptor tyrosine kinase with oncogenic properties overexpressed in PCa cases. Through the use of an alternative promoter, a truncated c-KIT protein (tr-KIT) of 30-50 kDa is generated, lacking the extracellular and transmembrane domain. Tr-KIT promotes the formation of a multi-molecular complex composed of Fyn, Plcγ1, and Sam68. Imatinib blocks the activity of full-length c-KIT but has no effect on tr-KIT. LNCaP is the human PCa cell line that shows tr-KIT overexpression and PC3 does not show tr-KIT overexpression. miR-128/193a- 5p/494 are miRNAs targeting FYN, PLCγ1, and SAM68 combinatorially. The study's question is: can miR-128/193a- 5p/494 be related to imatinib resistance in PCa?

Methods: LNCaP and PC3 cells were treated with imatinib in IC50 doses. Before and after imatinib administration, RNA was isolated and cDNA conversion was performed. By qPCR analysis, expression changes of tr-KIT specific pathway elements and miR-128/193a-5p/494 were analyzed before and after imatinib administration.

Results: After imatinib administration, miR-128/193a-5p/494 were significantly overexpressed in LNCaP cells while downregulated significantly in PC3 cells (p<0.05). Also, FYN was upregulated in LNCaP cells (p<0.05) but there was no change in PC3 after imatinib administration.

Conclusion: Especially upregulation of FYN may sponge miR128/193a-5p/494 and downregulate their transcriptional activity in LNCaP cells having tr-KIT activity. So, miR-128/193a-5p/494 may have a critical role in imatinib resistance via a tr-KIT pathway.

Keywords: Prostate cancer, imatinib resistance, truncated KIT (tr-KIT), FYN, miRNA sponging

Graphical Abstract

[1]
Yegnasubramanian, S. Prostate cancer epigenetics and its clinical implications. Asian J. Androl., 2016, 18(4), 549-558.
[http://dx.doi.org/10.4103/1008-682X.179859] [PMID: 27212125]
[2]
Imura, M.; Kojima, Y.; Kubota, Y.; Hamakawa, T.; Yasui, T.; Sasaki, S.; Hayashi, Y.; Kohri, K. Regulation of cell proliferation through a KIT-mediated mechanism in benign prostatic hyperplasia. Prostate, 2012, 72(14), 1506-1513.
[http://dx.doi.org/10.1002/pros.22500] [PMID: 22314612]
[3]
Di Lorenzo, G.; Autorino, R.; D’Armiento, F.P.; Mignogna, C.; De Laurentiis, M.; De Sio, M.; D’Armiento, M.; Damiano, R.; Vecchio, G.; De Placido, S. Expression of proto-oncogene c-kit in high risk prostate cancer. Eur. J. Surg. Oncol., 2004, 30(9), 987-992.
[http://dx.doi.org/10.1016/j.ejso.2004.07.017] [PMID: 15498646]
[4]
Ergün, S.; Altay, D.U.; Güneş, S.; Büyükalpelli, R.; Karahan, S.C.; Tomak, L.; Abur, Ü. Tr-KIT/c-KIT ratio in renal cell carcinoma. Mol. Biol. Rep., 2019, 46(5), 5287-5294.
[http://dx.doi.org/10.1007/s11033-019-04985-3] [PMID: 31342295]
[5]
Roskoski, R. Jr Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor. Biochem. Biophys. Res. Commun., 2005, 338(3), 1307-1315.
[http://dx.doi.org/10.1016/j.bbrc.2005.09.150] [PMID: 16226710]
[6]
Cardoso, H.J.; Figueira, M.I.; Socorro, S. The stem cell factor (SCF)/c-KIT signalling in testis and prostate cancer. J. Cell Commun. Signal., 2017, 11(4), 297-307.
[http://dx.doi.org/10.1007/s12079-017-0399-1] [PMID: 28656507]
[7]
Paronetto, M.P.; Venables, J.P.; Elliott, D.J.; Geremia, R.; Rossi, P.; Sette, C. Tr-kit promotes the formation of a multimolecular complex composed by Fyn, PLCgamma1 and Sam68. Oncogene, 2003, 22(54), 8707-8715.
[http://dx.doi.org/10.1038/sj.onc.1207016] [PMID: 14647465]
[8]
Mol, C.D.; Dougan, D.R.; Schneider, T.R.; Skene, R.J.; Kraus, M.L.; Scheibe, D.N.; Snell, G.P.; Zou, H.; Sang, B-C.; Wilson, K.P. Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J. Biol. Chem., 2004, 279(30), 31655-31663.
[http://dx.doi.org/10.1074/jbc.M403319200] [PMID: 15123710]
[9]
Friedman, Y.; Naamati, G.; Linial, M. MiRror: A combinatorial analysis web tool for ensembles of microRNAs and their targets. Bioinformatics, 2010, 26(15), 1920-1921.
[http://dx.doi.org/10.1093/bioinformatics/btq298] [PMID: 20529892]
[10]
Gao, L.; Jin, H.J.; Zhang, D.; Lin, Q. Silencing circRNA_001937 may inhibit cutaneous squamous cell carcinoma proliferation and induce apoptosis by preventing the sponging of the miRNA-597-3p/FOSL2 pathway. Int. J. Mol. Med., 2020, 46(5), 1653-1660.
[http://dx.doi.org/10.3892/ijmm.2020.4723] [PMID: 33000177]
[11]
Saito, Y.D.; Jensen, A.R.; Salgia, R.; Posadas, E.M. Fyn: A novel molecular target in cancer. Cancer, 2010, 116(7), 1629-1637.
[http://dx.doi.org/10.1002/cncr.24879] [PMID: 20151426]
[12]
Elias, D.; Ditzel, H.J. Fyn is an important molecule in cancer pathogenesis and drug resistance. Pharmacol. Res., 2015, 100, 250-254.
[http://dx.doi.org/10.1016/j.phrs.2015.08.010] [PMID: 26305432]
[13]
Zhang, S.; Qi, Q.; Chan, C.B.; Zhou, W.; Chen, J.; Luo, H.R.; Appin, C.; Brat, D.J.; Ye, K. Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity. Cell Death Differ., 2016, 23(1), 52-63.
[http://dx.doi.org/10.1038/cdd.2015.66] [PMID: 26001218]
[14]
Liu, G.; Ji, L.; Ke, M.; Ou, Z.; Tang, N.; Li, Y. miR-125a-3p is responsible for chemosensitivity in PDAC by inhibiting epithelial-mesenchymal transition via Fyn. Biomed. Pharmacother., 2018, 106, 523-531.
[http://dx.doi.org/10.1016/j.biopha.2018.06.114] [PMID: 29990840]
[15]
Elias, D.; Vever, H.; Lænkholm, A.V.; Gjerstorff, M.F.; Yde, C.W.; Lykkesfeldt, A.E.; Ditzel, H.J. Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy. Oncogene, 2015, 34(15), 1919-1927.
[http://dx.doi.org/10.1038/onc.2014.138] [PMID: 24882577]
[16]
Lee, G-H.; Yoo, K-C.; An, Y.; Lee, H-J.; Lee, M.; Uddin, N.; Kim, M-J.; Kim, I-G.; Suh, Y.; Lee, S-J. FYN promotes mesenchymal pheno-types of basal type breast cancer cells through STAT5/NOTCH2 signaling node. Oncogene, 2018, 37(14), 1857-1868.
[http://dx.doi.org/10.1038/s41388-017-0114-y] [PMID: 29348460]
[17]
Wang, X.; Wen, J.; Li, R.; Qiu, G.; Zhou, L.; Wen, X. Gene expression profiling analysis of castration-resistant prostate cancer. Med. Sci. Monit., 2015, 21, 205-212.
[http://dx.doi.org/10.12659/MSM.891193] [PMID: 25592164]
[18]
Posadas, E.M.; Al-Ahmadie, H.; Robinson, V.L.; Jagadeeswaran, R.; Otto, K.; Kasza, K.E.; Tretiakov, M.; Siddiqui, J.; Pienta, K.J.; Stadler, W.M.; Rinker-Schaeffer, C.; Salgia, R. FYN is overexpressed in human prostate cancer. BJU Int., 2009, 103(2), 171-177.
[http://dx.doi.org/10.1111/j.1464-410X.2008.08009.x] [PMID: 18990162]
[19]
Gururajan, M.; Cavassani, K.A.; Sievert, M.; Duan, P.; Lichterman, J.; Huang, J-M.; Smith, B.; You, S.; Nandana, S.; Chu, G.C-Y.; Mink, S.; Josson, S.; Liu, C.; Morello, M.; Jones, L.W.; Kim, J.; Freeman, M.R.; Bhowmick, N.; Zhau, H.E.; Chung, L.W.; Posadas, E.M. SRC family kinase FYN promotes the neuroendocrine phenotype and visceral metastasis in advanced prostate cancer. Oncotarget, 2015, 6(42), 44072-44083.
[http://dx.doi.org/10.18632/oncotarget.6398] [PMID: 26624980]
[20]
Jensen, A.R.; David, S.Y.; Liao, C.; Dai, J.; Keller, E.T.; Al-Ahmadie, H.; Dakin-Haché, K.; Usatyuk, P.; Sievert, M.F.; Paner, G.P.; Yala, S.; Cervantes, G.M.; Natarajan, V.; Salgia, R.; Posadas, E.M. Fyn is downstream of the HGF/MET signaling axis and affects cellular shape and tropism in PC3 cells. Clin. Cancer Res., 2011, 17(10), 3112-3122.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-1264] [PMID: 21364031]
[21]
Guo, Y.; Yue, P.; Wang, Y.; Chen, G.; Li, Y. PCAT-1 contributes to cisplatin resistance in gastric cancer through miR-128/ZEB1 axis. Biomed. Pharmacother., 2019, 118, 109255.
[http://dx.doi.org/10.1016/j.biopha.2019.109255] [PMID: 31352238]
[22]
Zhu, Y.; Yu, F.; Jiao, Y.; Feng, J.; Tang, W.; Yao, H.; Gong, C.; Chen, J.; Su, F.; Zhang, Y.; Song, E. Reduced miR-128 in breast tumor-initiating cells induces chemotherapeutic resistance via Bmi-1 and ABCC5. Clin. Cancer Res., 2011, 17(22), 7105-7115.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-0071] [PMID: 21953503]
[23]
Zhou, X.; Yue, G.G-L.; Liu, M.; Zuo, Z.; Lee, J.K-M.; Li, M.; Tsui, S.K-W.; Fung, K-P.; Sun, H.; Pu, J.; Lau, C.B. Eriocalyxin B, a natural diterpenoid, inhibited VEGF-induced angiogenesis and diminished angiogenesis-dependent breast tumor growth by suppressing VEGFR-2 signaling. Oncotarget, 2016, 7(50), 82820-82835.
[http://dx.doi.org/10.18632/oncotarget.12652] [PMID: 27756875]
[24]
Cao, X-Z.; Bin, H.; Zang, Z-N. MiR-128 suppresses the growth of thyroid carcinoma by negatively regulating SPHK1. Biomed. Pharmacother., 2019, 109, 1960-1966.
[http://dx.doi.org/10.1016/j.biopha.2018.08.052] [PMID: 30551451]
[25]
Lo, U-G.; Pong, R-C.; Yang, D.; Gandee, L.; Hernandez, E.; Dang, A.; Lin, C-J.; Santoyo, J.; Ma, S.; Sonavane, R.; Huang, J.; Tseng, S.F.; Moro, L.; Arbini, A.A.; Kapur, P.; Raj, G.V.; He, D.; Lai, C.H.; Lin, H.; Hsieh, J.T. IFNγ-induced IFIT5 promotes epithelial-to-Mesenchymal transition in prostate Cancer via miRNA processing. Cancer Res., 2019, 79(6), 1098-1112.
[PMID: 30504123]
[26]
Khan, A.P.; Poisson, L.M.; Bhat, V.B.; Fermin, D.; Zhao, R.; Kalyana-Sundaram, S.; Michailidis, G.; Nesvizhskii, A.I.; Omenn, G.S.; Chinnaiyan, A.M.; Sreekumar, A. Quantitative proteomic profiling of prostate cancer reveals a role for miR-128 in prostate cancer. Mol. Cell. Proteomics, 2010, 9(2), 298-312.
[http://dx.doi.org/10.1074/mcp.M900159-MCP200] [PMID: 19955085]
[27]
Hao, S.D.; Ma, J.X.; Liu, Y.; Liu, P.J.; Qin, Y. Long non-coding TUG1 accelerates prostate cancer progression through regulating miR-128-3p/YES1 axis. Eur. Rev. Med. Pharmacol. Sci., 2020, 24(2), 619-632.
[PMID: 32016963]
[28]
Yang, Y.; Zhou, L.; Lu, L.; Wang, L.; Li, X.; Jiang, P.; Chan, L.K.; Zhang, T.; Yu, J.; Kwong, J.; Cheung, T.H.; Chung, T.; Mak, K.; Sun, H.; Wang, H. A novel miR-193a-5p-YY1-APC regulatory axis in human endometrioid endometrial adenocarcinoma. Oncogene, 2013, 32(29), 3432-3442.
[http://dx.doi.org/10.1038/onc.2012.360] [PMID: 22907428]
[29]
Yu, T.; Li, J.; Yan, M.; Liu, L.; Lin, H.; Zhao, F.; Sun, L.; Zhang, Y.; Cui, Y.; Zhang, F.; Li, J.; He, X.; Yao, M. MicroRNA-193a-3p and -5p suppress the metastasis of human non-small-cell lung cancer by downregulating the ERBB4/PIK3R3/mTOR/S6K2 signaling pathway. Oncogene, 2015, 34(4), 413-423.
[http://dx.doi.org/10.1038/onc.2013.574] [PMID: 24469061]
[30]
Zhou, J.; Duan, H.; Xie, Y.; Ning, Y.; Zhang, X.; Hui, N.; Wang, C.; Zhang, J.; Zhou, J. MiR-193a-5p targets the coding region of AP-2α mRNA and induces cisplatin resistance in bladder cancers. J. Cancer, 2016, 7(12), 1740-1746.
[http://dx.doi.org/10.7150/jca.15620] [PMID: 27698912]
[31]
Jacques, C.; Calleja, L.R.; Baud’huin, M.; Quillard, T.; Heymann, D.; Lamoureux, F.; Ory, B. miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors. Oncotarget, 2016, 7(34), 54503-54514.
[http://dx.doi.org/10.18632/oncotarget.10950] [PMID: 27486986]
[32]
Yang, Z.; Qu, C-B.; Zhang, Y.; Zhang, W-F.; Wang, D-D.; Gao, C-C.; Ma, L.; Chen, J-S.; Liu, K-L.; Zheng, B.; Zhang, X.H.; Zhang, M.L.; Wang, X.L.; Wen, J.K.; Li, W. Dysregulation of p53-RBM25-mediated circAMOTL1L biogenesis contributes to prostate cancer progression through the circAMOTL1L-miR-193a-5p-Pcdha pathway. Oncogene, 2019, 38(14), 2516-2532.
[http://dx.doi.org/10.1038/s41388-018-0602-8] [PMID: 30531834]
[33]
Yang, Z.; Chen, J-S.; Wen, J-K.; Gao, H-T.; Zheng, B.; Qu, C-B.; Liu, K-L.; Zhang, M-L.; Gu, J-F.; Li, J-D.; Zhang, Y.P.; Li, W.; Wang, X.L.; Zhang, Y. Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel. J. Exp. Clin. Cancer Res., 2017, 36(1), 178.
[http://dx.doi.org/10.1186/s13046-017-0649-3] [PMID: 29216925]
[34]
Song, L.; Liu, D.; Wang, B.; He, J.; Zhang, S.; Dai, Z.; Ma, X.; Wang, X. miR-494 suppresses the progression of breast cancer in vitro by targeting CXCR4 through the Wnt/β-catenin signaling pathway. Oncol. Rep., 2015, 34(1), 525-531.
[http://dx.doi.org/10.3892/or.2015.3965] [PMID: 25955111]
[35]
Li, N.; Zhao, X.; Wang, L.; Zhang, S.; Cui, M.; He, J. miR-494 suppresses tumor growth of epithelial ovarian carcinoma by targeting IGF1R. Tumour Biol., 2016, 37(6), 7767-7776.
[http://dx.doi.org/10.1007/s13277-015-4603-8] [PMID: 26695144]
[36]
Li, X.T.; Wang, H.Z.; Wu, Z.W.; Yang, T.Q.; Zhao, Z.H.; Chen, G.L.; Xie, X.S.; Li, B.; Wei, Y.X.; Huang, Y.L.; Zhou, Y.X.; Du, Z.W. miR-494-3p regulates cellular proliferation, invasion, migration, and apoptosis by PTEN/AKT signaling in human glioblastoma cells. Cell. Mol. Neurobiol., 2015, 35(5), 679-687.
[http://dx.doi.org/10.1007/s10571-015-0163-0] [PMID: 25662849]
[37]
Liu, K.; Liu, S.; Zhang, W.; Jia, B.; Tan, L.; Jin, Z.; Liu, Y. miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN. Oncol. Rep., 2015, 34(2), 1003-1010.
[http://dx.doi.org/10.3892/or.2015.4030] [PMID: 26045065]
[38]
Zhu, L.; Wang, X.; Wang, T.; Zhu, W.; Zhou, X. miR-494-3p promotes the progression of endometrial cancer by regulating the PTEN/PI3K/AKT pathway. Mol. Med. Rep., 2019, 19(1), 581-588.
[PMID: 30431102]
[39]
Liu, Y.; Li, X.; Zhu, S.; Zhang, J.G.; Yang, M.; Qin, Q.; Deng, S.C.; Wang, B.; Tian, K.; Liu, L.; Niu, Y.; Wang, C.Y.; Zhao, G. Ectopic expression of miR-494 inhibited the proliferation, invasion and chemoresistance of pancreatic cancer by regulating SIRT1 and c-Myc. Gene Ther., 2015, 22(9), 729-738.
[http://dx.doi.org/10.1038/gt.2015.39] [PMID: 25965392]
[40]
Yang, Y.K.; Xi, W.Y.; Xi, R.X.; Li, J.Y.; Li, Q.; Gao, Y.E. MicroRNA-494 promotes cervical cancer proliferation through the regulation of PTEN. Oncol. Rep., 2015, 33(5), 2393-2401.
[http://dx.doi.org/10.3892/or.2015.3821] [PMID: 25738254]
[41]
Zhu, J.; Sun, C.; Wang, L.; Xu, M.; Zang, Y.; Zhou, Y.; Liu, X.; Tao, W.; Xue, B.; Shan, Y.; Yang, D. Targeting survivin using a combination of miR-494 and survivin shRNA has synergistic effects on the suppression of prostate cancer growth. Mol. Med. Rep., 2016, 13(2), 1602-1610.
[http://dx.doi.org/10.3892/mmr.2015.4739] [PMID: 26718651]
[42]
Guo, K.; Liang, Z.; Li, F.; Wang, H. Comparison of miRNA and gene expression profiles between metastatic and primary prostate cancer. Oncol. Lett., 2017, 14(5), 6085-6090.
[http://dx.doi.org/10.3892/ol.2017.6969] [PMID: 29113250]
[43]
Valera, V.A.; Parra-Medina, R.; Walter, B.A.; Pinto, P.; Merino, M.J. microRNA expression profiling in young prostate cancer patients. J. Cancer, 2020, 11(14), 4106-4114.
[http://dx.doi.org/10.7150/jca.37842] [PMID: 32368293]
[44]
Shen, P.F.; Chen, X.Q.; Liao, Y.C.; Chen, N.; Zhou, Q.; Wei, Q.; Li, X.; Wang, J.; Zeng, H. MicroRNA-494-3p targets CXCR4 to suppress the proliferation, invasion, and migration of prostate cancer. Prostate, 2014, 74(7), 756-767.
[http://dx.doi.org/10.1002/pros.22795] [PMID: 24644030]