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Current Cancer Drug Targets

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

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Research Article

Combined Inhibition of KIF11 and KIF15 as an Effective Therapeutic Strategy for Gastric Cancer

Author(s): Ruo-Fei Sun, Na He, Geng-Yuan Zhang, Ze-Yuan Yu, Lian-Shun Li, Zhi-Jian Ma and Zuo-Yi Jiao*

Volume 23, Issue 4, 2023

Published on: 14 November, 2022

Page: [293 - 306] Pages: 14

DOI: 10.2174/1568009622666220616122846

Price: $65

Abstract

Background: Novel therapeutic strategies are urgently required to improve clinical outcomes of gastric cancer (GC). KIF15 cooperates with KIF11 to promote bipolar spindle assembly and formation, which is essential for proper sister chromatid segregation. Therefore, we speculated that the combined inhibition of KIF11 and KIF15 might be an effective strategy for GC treatment. Hence, to test this hypothesis, we aimed to evaluate the combined therapeutic effect of KIF15 inhibitor KIF15- IN-1 and KIF11 inhibitor ispinesib in GC.

Methods: We validated the expression of KIF11 and KIF15 in GC tissues using immunohistochemistry and immunoblotting. Next, we determined the effects of KIF11 or KIF15 knockout on the proliferation of GC cell lines. Finally, we investigated the combined effects of the KIF11 and KIF15 inhibitors both in vitro and in vivo.

Results: KIF11 and KIF15 were overexpressed in GC tissues than in the adjacent normal tissues. Knockout of either KIF11 or KIF15 inhibited the proliferative and clonogenic abilities of GC cells. We found that the KIF15 knockout significantly increased ispinesib sensitivity in GC cells, while its overexpression showed the opposite effect. Further, using KIF15-IN-1 and ispinesib together had a synergistic effect on the antitumor proliferation of GC both in vitro and in vivo.

Conclusion: This study shows that the combination therapy of inhibiting KIF11 and KIF15 might be an effective therapeutic strategy against gastric cancer.

Keywords: Gastric cancer, KIF11, KIF15, KIF15-IN-1, ispinesib, inhibition.

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[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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