Artículos de revistas
Potential Antileukemia Effect And Structural Analyses Of Srpk Inhibition By N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) Isonicotinamide (srpin340)
Registro en:
Plos One. Public Library Of Science, v. 10, n. 8, p. , 2015.
19326203
10.1371/journal.pone.0134882
2-s2.0-84941985106
Institución
Resumen
Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates. Copyright: © 2015 Siqueira et al. 10 8
Wang, E.T., Sandberg, R., Luo, S., Khrebtukova, I., Zhang, L., Mayr, C., Alternative isoform regulation in human tissue transcriptomes (2008) Nature., 456, pp. 470-476. , 18978772 Fedorov, O., Huber, K., Eisenreich, A., Filippakopoulos, P., King, O., Bullock, A.N., Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing (2011) Chem Biol., 18, pp. 67-76. , 21276940 Harper, S.J., Bates, D.O., VEGF-A splicing: The key to anti-angiogenic therapeutics? (2008) Nat Rev Cancer., 8, pp. 880-887. , 18923433 Ward, A.J., Cooper, T.A., The pathobiology of splicing (2010) J Pathol., 220, pp. 152-163. , 19918805 Bourgeois, C.F., Lejeune, F., Stevenin, J., Broad specificity of SR (serine/arginine) proteins in the regulation of alternative splicing of pre-messenger RNA (2004) Prog Nucleic Acid Res Mol Biol., 78, pp. 37-88. , 15210328 Wahl, M.C., Will, C.L., Luhrmann, R., The spliceosome: Design principles of a dynamic RNP machine (2009) Cell., 136, pp. 701-718. , 19239890 Long, J.C., Caceres, J.F., The SR protein family of splicing factors: Master regulators of gene expression (2009) Biochem J., 417, pp. 15-27. , 19061484 House, A.E., Lynch, K.W., Regulation of alternative splicing: More than just the ABCs (2008) J Biol Chem., 283, pp. 1217-1221. , 18024429 Cho, S., Hoang, A., Chakrabarti, S., Huynh, N., Huang, D.B., Ghosh, G., The SRSF1 linker induces semi-conservative ESE binding by cooperating with the RRMs (2011) Nucleic Acids Res., 39, pp. 9413-9421. , 21852328 Giannakouros, T., Nikolakaki, E., Mylonis, I., Georgatsou, E., Serine-arginine protein kinases: A small protein kinase family with a large cellular presence (2011) FEBS J., 278, pp. 570-586. , 21205200 Zhong, X.Y., Ding, J.H., Adams, J.A., Ghosh, G., Fu, X.D., Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones (2009) Genes Dev., 23, pp. 482-495. , 19240134 Zhou, Z., Fu, X.D., Regulation of splicing by SR proteins and SR protein-specific kinases (2013) Chromosoma., 122, pp. 191-207. , 23525660 Wong, K.K., Engelman, J.A., Cantley, L.C., Targeting the PI3K signaling pathway in cancer (2010) Curr Opin Genet Dev., 20, pp. 87-90. , 20006486 Courtney, K.D., Corcoran, R.B., Engelman, J.A., The PI3K pathway as drug target in human cancer (2010) J Clin Oncol., 28, pp. 1075-1083. , 20085938 Jang, S.W., Yang, S.J., Ehlen, A., Dong, S., Khoury, H., Chen, J., Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1 (2008) Cancer Res., 68, pp. 4559-4570. , 18559500 Aubol, B.E., Plocinik, R.M., Hagopian, J.C., Ma, C.T., McGlone, M.L., Bandyopadhyay, R., Partitioning RS domain phosphorylation in an SR protein through the CLK and SRPK protein kinases (2013) J Mol Biol., 425, pp. 2894-2909. , 23707382 Wang, P., Zhou, Z., Hu, A., Ponte De Albuquerque, C., Zhou, Y., Hong, L., Both decreased and increased SRPK1 levels promote cancer by interfering with PHLPP-mediated dephosphorylation of Akt (2014) Mol Cell., 54, pp. 378-391. , 24703948 Hayes, G.M., Carrigan, P.E., Beck, A.M., Miller, L.J., Targeting the RNA splicing machinery as a novel treatment strategy for pancreatic carcinoma (2006) Cancer Res., 66, pp. 3819-3827. , 16585209 Hayes, G.M., Carrigan, P.E., Miller, L.J., Serine-arginine protein kinase 1 overexpression is associated with tumorigenic imbalance in mitogen-activated protein kinase pathways in breast, colonic, and pancreatic carcinomas (2007) Cancer Res., 67, pp. 2072-2080. , 17332336 Gout, S., Brambilla, E., Boudria, A., Drissi, R., Lantuejoul, S., Gazzeri, S., Abnormal expression of the pre-mRNA splicing regulators SRSF1, SRSF2, SRPK1 and SRPK2 in non small cell lung carcinoma (2012) PLoS One., 7. , 23071587 Wu, Q., Chang, Y., Zhang, L., Zhang, Y., Tian, T., Feng, G., Srpk1 dissimilarly impacts on the growth, metastasis, chemosensitivity and angiogenesis of glioma in normoxic and hypoxic conditions (2013) J Cancer., 4, pp. 727-735. , 24312143 Gammons, M.V., Lucas, R., Dean, R., Coupland, S.E., Oltean, S., Bates, D.O., Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma (2014) Br J Cancer., 111, pp. 477-485. , 25010863 Salesse, S., Dylla, S.J., Verfaillie, C.M., P210BCR/ABL-induced alteration of pre-mRNA splicing in primary human CD34+ hematopoietic progenitor cells (2004) Leukemia., 18, pp. 727-733. , 14961028 Hishizawa, M., Imada, K., Sakai, T., Ueda, M., Hori, T., Uchiyama, T., Serological identification of adult T-cell leukaemia-associated antigens (2005) Br J Haematol., 130, pp. 382-390. , 16042687 Fukuhara, T., Hosoya, T., Shimizu, S., Sumi, K., Oshiro, T., Yoshinaka, Y., Utilization of host SR protein kinases and RNA-splicing machinery during viral replication (2006) Proc Natl Acad Sci U S A., 103, pp. 11329-11333. , 16840555 Hagiwara, M., Fukuhara, T., Suzuki, M., Hosoya, T., (2009) Method for Controlling Protein Phosphorilation, and Antiviral Agents Whose Active Ingredients Comprise Agents That Control SR Protein Activity, , United States Patent Karakama, Y., Sakamoto, N., Itsui, Y., Nakagawa, M., Tasaka-Fujita, M., Nishimura-Sakurai, Y., Inhibition of hepatitis C virus replication by a specific inhibitor of serine-arginine-rich protein kinase (2010) Antimicrob Agents Chemother., 54, pp. 3179-3186. , 20498328 Anwar, A., Hosoya, T., Leong, K.M., Onogi, H., Okuno, Y., Hiramatsu, T., The kinase inhibitor SFV785 dislocates dengue virus envelope protein from the replication complex and blocks virus assembly (2011) PLoS One., 6. , 21858043 Nowak, D.G., Amin, E.M., Rennel, E.S., Hoareau-Aveilla, C., Gammons, M., Damodoran, G., Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: A novel therapeutic strategy for angiogenesis (2010) J Biol Chem., 285, pp. 5532-5540. , 19906640 Gammons, M.V., Dick, A.D., Harper, S.J., Bates, D.O., SRPK1 inhibition modulates VEGF splicing to reduce pathological neovascularization in a rat model of retinopathy of prematurity (2013) Invest Ophthalmol Vis Sci., 54, pp. 5797-5806. , 23761094 Dong, Z., Noda, K., Kanda, A., Fukuhara, J., Ando, R., Murata, M., Specific inhibition of serine/argininerich protein kinase attenuates choroidal neovascularization (2013) Mol Vis., 19, pp. 536-543. , 23559848 Amin, E.M., Oltean, S., Hua, J., Gammons, M.V., Hamdollah-Zadeh, M., Welsh, G.I., WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing (2011) Cancer Cell., 20, pp. 768-780. , 22172722 Carneiro, F.R., Silva, T.C., Alves, A.C., Haline-Vaz, T., Gozzo, F.C., Zanchin, N.I., Spectroscopic characterization of the tumor antigen NY-REN-21 and identification of heterodimer formation with SCAND1 (2006) Biochem Biophys Res Commun., 343, pp. 260-268. , 16540086 Silva, K.P., Seraphim, T.V., Borges, J.C., Structural and functional studies of Leishmania braziliensis Hsp90 (2013) Biochim Biophys Acta., 1834, pp. 351-361. , 22910377 Breneman, C.M., Wiberg, K.B., Determining atom-centered monopoles from molecular electrostatic potentials (1990) The Need for High Sampling Density in Formamide Conformational Analysis. Journal of Computational Chemistry., 11, pp. 361-373 Schmidt, M.W., Baldridge, K.K., Boatz, J.A., Elbert, S.T., Gordon, M.S., Jensen, J.H., General atomic and molecular electronic structure system (1993) J Comput Chem., 14, pp. 1347-1363 Schuttelkopf, A.W., Van Aalten, D.M., PRODRG: A tool for high-throughput crystallography of protein-ligand complexes (2004) Acta Crystallogr D Biol Crystallogr., 60, pp. 1355-1363. , 15272157 Ngo, J.C., Giang, K., Chakrabarti, S., Ma, C.T., Huynh, N., Hagopian, J.C., A sliding docking interaction is essential for sequential and processive phosphorylation of an SR protein by SRPK1 (2008) Mol Cell., 29, pp. 563-576. , 18342604 Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., AutoDock4 and Auto-DockTools4: Automated docking with selective receptor flexibility (2009) J Comput Chem., 30, pp. 2785-2791. , 19399780 Huey, R., Morris, G.M., Olson, A.J., Goodsell, D.S., A semiempirical free energy force field with charge-based desolvation (2007) J Comput Chem., 28, pp. 1145-1152. , 17274016 Pronk, S., Pall, S., Schulz, R., Larsson, P., Bjelkmar, P., Apostolov, R., GROMACS 4.5: A high-throughput and highly parallel open source molecular simulation toolkit (2013) Bioinformatics., 29, pp. 845-854. , 23407358 Oostenbrink, C., Villa, A., Mark, A.E., Van Gunsteren, W.F., A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6 (2004) J Comput Chem., 25, pp. 1656-1676. , 15264259 Gammons, M.V., Fedorov, O., Ivison, D., Du, C., Clark, T., Hopkins, C., Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD (2013) Invest Ophthalmol Vis Sci., 54, pp. 6052-6062. , 23887803 Clery, A., Sinha, R., Anczukow, O., Corrionero, A., Moursy, A., Daubner, G.M., Isolated pseudo-RNA-recognition motifs of SR proteins can regulate splicing using a noncanonical mode of RNA recognition (2013) Proc Natl Acad Sci U S A., 110, pp. E2802-2811. , 23836656 Kim, H., Choi, K., Kang, H., Lee, S.Y., Chi, S.W., Lee, M.S., Identification of a novel function of CX-4945 as a splicing regulator (2014) PLoS One., 9. , 24743259 Zahler, A.M., Lane, W.S., Stolk, J.A., Roth, M.B., SR proteins: A conserved family of pre-mRNA splicing factors (1992) Genes Dev., 6, pp. 837-847. , 1577277 Wang, H.Y., Lin, W., Dyck, J.A., Yeakley, J.M., Songyang, Z., Cantley, L.C., SRPK2: A differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of premRNA splicing factors in mammalian cells (1998) J Cell Biol., 140, pp. 737-750. , 9472028 Odunsi, K., Mhawech-Fauceglia, P., Andrews, C., Beck, A., Amuwo, O., Lele, S., Elevated expression of the serine-arginine protein kinase 1 gene in ovarian cancer and its role in Cisplatin cytotoxicity in vitro (2012) PLoS One., 7. , 23236423 Naro, C., Sette, C., Phosphorylation-mediated regulation of alternative splicing in cancer (2013) Int J Cell Biol., 2013, p. 151839. , 24069033 Fukuhara, T., Hosoya, T., Shimizu, S., Sumi, K., Oshiro, T., Yoshinaka, Y., Utilization of host SR protein kinases and RNA-splicing machinery during viral replication (2006) Proc Natl Acad Sci U S A., 103, pp. 11329-11333. , 16840555 Hong, Y., Jang, S.W., Ye, K., The N-terminal fragment from caspase-cleaved serine/arginine protein-specific kinase2 (SRPK2) translocates into the nucleus and promotes apoptosis (2011) J Biol Chem., 286, pp. 777-786. , 21056976 Knight, Z.A., Lin, H., Shokat, K.M., Targeting the cancer kinome through polypharmacology (2010) Nat Rev Cancer., 10, pp. 130-137. , 20094047 Aubol, B.E., Nolen, B., Shaffer, J., Ghosh, G., Adams, J.A., Novel destabilization of nucleotide binding by the gamma phosphate of ATP in the yeast SR protein kinase Sky1p (2003) Biochemistry., 42, pp. 12813-12820. , 14596595 Mavrou, A., Brakspear, K., Hamdollah-Zadeh, M., Damodaran, G., Babaei-Jadidi, R., Oxley, J., Serinearginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer (2014) Oncogene. Bustin, S.A., Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays (2000) J Mol Endocrinol., 25, pp. 169-193. , 11013345 Wong, M.L., Medrano, J.F., Real-time PCR for mRNA quantitation (2005) Biotechniques., 39, pp. 75-85. , 16060372