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当代肿瘤药物靶点

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

联合抑制KIF11和KIF15是治疗胃癌的有效策略

卷 23, 期 4, 2023

发表于: 14 November, 2022

页: [293 - 306] 页: 14

弟呕挨: 10.2174/1568009622666220616122846

价格: $65

摘要

背景:为了提高胃癌的临床疗效,迫切需要新的治疗策略。KIF15与KIF11合作促进双极纺锤体的组装和形成,这对于姐妹染色单体的分离至关重要。因此,我们推测联合抑制KIF11和KIF15可能是治疗GC的有效策略。因此,为了验证这一假设,我们旨在评估KIF15抑制剂KIF15- in -1和KIF11抑制剂ispinesib在GC中的联合治疗效果。 方法:我们用免疫组织化学和免疫印迹法验证了KIF11和KIF15在胃癌组织中的表达。接下来,我们确定了KIF11或KIF15敲除对GC细胞系增殖的影响。最后,我们研究了KIF11和KIF15抑制剂在体外和体内的联合作用。 结果:KIF11和KIF15在胃癌组织中较邻近正常组织中过表达。敲除KIF11或KIF15均能抑制GC细胞的增殖和克隆能力。我们发现KIF15敲除显著提高了GC细胞中ispinesib的敏感性,而其过表达则表现出相反的效果。此外,KIF15-IN-1与ispinesib联合使用对GC体外和体内抗肿瘤增殖具有协同作用。 结论:本研究表明,抑制KIF11和KIF15的联合治疗可能是一种有效的胃癌治疗策略。

关键词: 胃癌,KIF11, KIF15, KIF15- in -1, ispinesib,抑制。

图形摘要
[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Wadhwa, R.; Song, S.; Lee, J.S.; Yao, Y.; Wei, Q.; Ajani, J.A. Gastric cancer-molecular and clinical dimensions. Nat. Rev. Clin. Oncol., 2013, 10(11), 643-655.
[http://dx.doi.org/10.1038/nrclinonc.2013.170] [PMID: 24061039]
[3]
Van Cutsem, E.; Sagaert, X.; Topal, B.; Haustermans, K.; Prenen, H. Gastric cancer. Lancet, 2016, 388(10060), 2654-2664.
[http://dx.doi.org/10.1016/S0140-6736(16)30354-3] [PMID: 27156933]
[4]
Theiss, C.; Meller, K. Taxol impairs anterograde axonal transport of microinjected horseradish peroxidase in dorsal root ganglia neurons in vitro. Cell Tissue Res., 2000, 299(2), 213-224.
[http://dx.doi.org/10.1007/s004410050019] [PMID: 10741462]
[5]
Lee, J.J.; Swain, S.M. Peripheral neuropathy induced by microtubule-stabilizing agents. J. Clin. Oncol., 2006, 24(10), 1633-1642.
[http://dx.doi.org/10.1200/JCO.2005.04.0543] [PMID: 16575015]
[6]
Hirokawa, N.; Noda, Y.; Okada, Y. Kinesin and dynein superfamily proteins in organelle transport and cell division. Curr. Opin. Cell Biol., 1998, 10(1), 60-73.
[http://dx.doi.org/10.1016/S0955-0674(98)80087-2] [PMID: 9484596]
[7]
Hirokawa, N.; Noda, Y.; Tanaka, Y.; Niwa, S. Kinesin superfamily motor proteins and intracellular transport. Nat. Rev. Mol. Cell Biol., 2009, 10(10), 682-696.
[http://dx.doi.org/10.1038/nrm2774] [PMID: 19773780]
[8]
El-Nassan, H.B. Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents. Eur. J. Med. Chem., 2013, 62, 614-631.
[http://dx.doi.org/10.1016/j.ejmech.2013.01.031] [PMID: 23434636]
[9]
Rath, O.; Kozielski, F. Kinesins and cancer. Nat. Rev. Cancer, 2012, 12(8), 527-539.
[http://dx.doi.org/10.1038/nrc3310] [PMID: 22825217]
[10]
Weil, D.; Garçon, L.; Harper, M.; Duménil, D.; Dautry, F.; Kress, M. Targeting the kinesin Eg5 to monitor siRNA transfection in mammalian cells. Biotechniques, 2002, 33(6), 1244-1248.
[http://dx.doi.org/10.2144/02336st01] [PMID: 12503308]
[11]
Liu, C.; Zhou, N.; Li, J.; Kong, J.; Guan, X.; Wang, X. Eg5 overexpression is predictive of poor prognosis in hepatocellular carcinoma patients. Dis. Markers, 2017, 2017, 2176460.
[http://dx.doi.org/10.1155/2017/2176460] [PMID: 28684886]
[12]
Jungwirth, G.; Yu, T.; Moustafa, M.; Rapp, C.; Warta, R.; Jungk, C.; Sahm, F.; Dettling, S.; Zweckberger, K.; Lamszus, K.; Senft, C.; Loehr, M.; Keßler, A.F.; Ketter, R.; Westphal, M.; Debus, J.; von Deimling, A.; Simon, M.; Unterberg, A.; Abdollahi, A.; Herold-Mende, C. Identification of KIF11 as a novel target in meningioma. Cancers (Basel), 2019, 11(4), 11.
[http://dx.doi.org/10.3390/cancers11040545] [PMID: 30991738]
[13]
Pei, Y.Y.; Li, G.C.; Ran, J.; Wan, X.H.; Wei, F.X.; Wang, L. Kinesin family member 11 enhances the self-renewal ability of breast cancer cells by participating in the wnt/β-catenin pathway. J. Breast Cancer, 2019, 22(4), 522-532.
[http://dx.doi.org/10.4048/jbc.2019.22.e51] [PMID: 31897327]
[14]
Imai, T.; Oue, N.; Nishioka, M.; Mukai, S.; Oshima, T.; Sakamoto, N.; Sentani, K.; Matsusaki, K.; Yoshida, K.; Yasui, W. Overexpression of KIF11 in gastric cancer with intestinal mucin phenotype. Pathobiology, 2017, 84(1), 16-24.
[http://dx.doi.org/10.1159/000447303] [PMID: 27459100]
[15]
Jordan, M.A.; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer, 2004, 4, 253-265.
[http://dx.doi.org/10.1038/nrc1317]
[16]
Sturgill, E.G.; Norris, S.R.; Guo, Y.; Ohi, R. Kinesin-5 inhibitor resistance is driven by kinesin-12. J. Cell Biol., 2016, 213(2), 213-227.
[http://dx.doi.org/10.1083/jcb.201507036] [PMID: 27091450]
[17]
Tanenbaum, M.E. Macůrek, L.; Janssen, A.; Geers, E.F.; Alvarez-Fernández, M.; Medema, R.H. Kif15 cooperates with EG5 to promote bipolar spindle assembly. Curr. Biol., 2009, 19(20), 1703-1711.
[http://dx.doi.org/10.1016/j.cub.2009.08.027] [PMID: 19818618]
[18]
Tanenbaum, M.E.; Medema, R.H. Mechanisms of centrosome separation and bipolar spindle assembly. Dev. Cell, 2010, 19(6), 797-806.
[http://dx.doi.org/10.1016/j.devcel.2010.11.011] [PMID: 21145497]
[19]
Milic, B.; Chakraborty, A.; Han, K.; Bassik, M.C.; Block, S.M. KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics. Proc. Natl. Acad. Sci. USA, 2018, 115(20), E4613-E4622.
[http://dx.doi.org/10.1073/pnas.1801242115] [PMID: 29703754]
[20]
Wang, J.; Cheng, P.; Pavlyukov, M.S.; Yu, H.; Zhang, Z.; Kim, S.H.; Minata, M.; Mohyeldin, A.; Xie, W.; Chen, D.; Goidts, V.; Frett, B.; Hu, W.; Li, H.; Shin, Y.J.; Lee, Y.; Nam, D.H.; Kornblum, H.I.; Wang, M.; Nakano, I. Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2. J. Clin. Invest., 2017, 127(8), 3075-3089.
[http://dx.doi.org/10.1172/JCI89092] [PMID: 28737508]
[21]
Anker, J.F.; Naseem, A.F.; Mok, H.; Schaeffer, A.J.; Abdulkadir, S.A.; Thumbikat, P. Multi-faceted immunomodulatory and tissue-tropic clinical bacterial isolate potentiates prostate cancer immunotherapy. Nat. Commun., 2018, 9(1), 1591.
[http://dx.doi.org/10.1038/s41467-018-03900-x] [PMID: 29686284]
[22]
Chou, T.C.; Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul., 1984, 22, 27-55.
[http://dx.doi.org/10.1016/0065-2571(84)90007-4] [PMID: 6382953]
[23]
Zhang, X.; Wang, Y.; Liu, X.; Zhao, A.; Yang, Z.; Kong, F.; Sun, L.; Yu, Y.; Jiang, L. KIF2A promotes the progression via AKT signaling pathway and is upregulated by transcription factor ETV4 in human gastric cancer. Biomed. Pharmacother., 2020, 125, 109840.
[http://dx.doi.org/10.1016/j.biopha.2020.109840] [PMID: 32106376]
[24]
Hu, G.; Yan, Z.; Zhang, C.; Cheng, M.; Yan, Y.; Wang, Y.; Deng, L.; Lu, Q.; Luo, S. FOXM1 promotes hepatocellular carcinoma progression by regulating KIF4A expression. J. Exp. Clin. Cancer Res., 2019, 38(1), 188.
[http://dx.doi.org/10.1186/s13046-019-1202-3] [PMID: 31072351]
[25]
Li, X.L.; Ji, Y.M.; Song, R.; Li, X.N.; Guo, L.S. KIF23 promotes gastric cancer by stimulating cell proliferation. Dis. Markers, 2019, 2019, 9751923.
[http://dx.doi.org/10.1155/2019/9751923] [PMID: 31007778]
[26]
Tao, J.; Sun, G.; Li, Q.; Zhi, X.; Li, Z.; He, Z.; Chen, H.; Zhou, A.; Ye, J.; Xu, G.; Guan, W.; Zhang, W. KIF15 promotes the evolution of gastric cancer cells through inhibition of reactive oxygen species-mediated apoptosis. J. Cell. Physiol., 2020, 235(12), 9388-9398.
[http://dx.doi.org/10.1002/jcp.29743] [PMID: 32342525]
[27]
Purcell, J.W.; Davis, J.; Reddy, M.; Martin, S.; Samayoa, K.; Vo, H.; Thomsen, K.; Bean, P.; Kuo, W.L.; Ziyad, S.; Billig, J.; Feiler, H.S.; Gray, J.W.; Wood, K.W.; Cases, S. Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer. Clin. Cancer Res., 2010, 16(2), 566-576.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1498] [PMID: 20068098]
[28]
Gampa, G.; Kenchappa, R.S.; Mohammad, A.S.; Parrish, K.E.; Kim, M.; Crish, J.F.; Luu, A.; West, R.; Hinojosa, A.Q.; Sarkaria, J.N.; Rosenfeld, S.S.; Elmquist, W.F. Enhancing brain retention of a kif11 inhibitor significantly improves its efficacy in a mouse model of glioblastoma. Sci. Rep., 2020, 10(1), 6524.
[http://dx.doi.org/10.1038/s41598-020-63494-7] [PMID: 32300151]
[29]
Good, J.A.; Wang, F.; Rath, O.; Kaan, H.Y.; Talapatra, S.K.; Podgórski, D.; MacKay, S.P.; Kozielski, F. Optimized S-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models. J. Med. Chem., 2013, 56(5), 1878-1893.
[http://dx.doi.org/10.1021/jm3014597] [PMID: 23394180]

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