Research article Special Issues

The impact of MCCK1, an inhibitor of IKBKE kinase, on acute B lymphocyte leukemia cells


  • Received: 03 February 2024 Revised: 27 February 2024 Accepted: 29 February 2024 Published: 05 March 2024
  • B-cell acute lymphoblastic leukemia (B-ALL) is a malignant blood disorder, particularly detrimental to children and adolescents, with recurrent or unresponsive cases contributing significantly to cancer-associated fatalities. IKBKE, associated with innate immunity, tumor promotion, and drug resistance, remains poorly understood in the context of B-ALL. Thus, this research aimed to explore the impact of the IKBKE inhibitor MCCK1 on B-ALL cells. The study encompassed diverse experiments, including clinical samples, in vitro and in vivo investigations. Quantitative real-time fluorescence PCR and protein blotting revealed heightened IKBKE mRNA and protein expression in B-ALL patients. Subsequent in vitro experiments with B-ALL cell lines demonstrated that MCCK1 treatment resulted in reduced cell viability and survival rates, with flow cytometry indicating cell cycle arrest. In vivo experiments using B-ALL mouse tumor models substantiated MCCK1's efficacy in impeding tumor proliferation. These findings collectively suggest that IKBKE, found to be elevated in B-ALL patients, may serve as a promising drug target, with MCCK1 demonstrating potential for inducing apoptosis in B-ALL cells both in vitro and in vivo.

    Citation: Shuangshuang Wen, Peng Zhao, Siyu Chen, Bo Deng, Qin Fang, Jishi Wang. The impact of MCCK1, an inhibitor of IKBKE kinase, on acute B lymphocyte leukemia cells[J]. Mathematical Biosciences and Engineering, 2024, 21(4): 5164-5180. doi: 10.3934/mbe.2024228

    Related Papers:

  • B-cell acute lymphoblastic leukemia (B-ALL) is a malignant blood disorder, particularly detrimental to children and adolescents, with recurrent or unresponsive cases contributing significantly to cancer-associated fatalities. IKBKE, associated with innate immunity, tumor promotion, and drug resistance, remains poorly understood in the context of B-ALL. Thus, this research aimed to explore the impact of the IKBKE inhibitor MCCK1 on B-ALL cells. The study encompassed diverse experiments, including clinical samples, in vitro and in vivo investigations. Quantitative real-time fluorescence PCR and protein blotting revealed heightened IKBKE mRNA and protein expression in B-ALL patients. Subsequent in vitro experiments with B-ALL cell lines demonstrated that MCCK1 treatment resulted in reduced cell viability and survival rates, with flow cytometry indicating cell cycle arrest. In vivo experiments using B-ALL mouse tumor models substantiated MCCK1's efficacy in impeding tumor proliferation. These findings collectively suggest that IKBKE, found to be elevated in B-ALL patients, may serve as a promising drug target, with MCCK1 demonstrating potential for inducing apoptosis in B-ALL cells both in vitro and in vivo.



    加载中


    [1] I. Aldoss, A. S. Stein, Advances in adult acute lymphoblastic leukemia therapy, Leuk. Lymphoma, 59 (2017), 1033–1050. http://dx.doi.org/10.1080/10428194.2017.1354372 doi: 10.1080/10428194.2017.1354372
    [2] Y. Jin, Z. Lu, K. Ding, J. Li, X. Du, C. Chen, et al., Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: Inactivation of the NF-$\kappa$B pathway and generation of reactive oxygen species, Cancer Res., 70 (2010), 2516–2527. http://dx.doi.org/10.1158/0008-5472.CAN-09-3950 doi: 10.1158/0008-5472.CAN-09-3950
    [3] S. Thota, A. Advani, Inotuzumab ozogamicin in relapsed B-cell acute lymphoblastic leukemia, Eur. J. Haematol., 98 (2017), 425–434. http://dx.doi.org/10.1111/ejh.12862 doi: 10.1111/ejh.12862
    [4] N. Gokbuget, H. Dombret, J. M. Ribera, A. K. Fielding, A. Advani, R. Bassan, et al., International reference analysis of outcomes in adults with b-precursor ph-negative relapsed/refractory acute lymphoblastic leukemia, Haematologica, 101 (2016), 1524–1533. http://dx.doi.org/10.3324/haematol.2016.144311 doi: 10.3324/haematol.2016.144311
    [5] D. Liu, J. Zhao, Y. Song, X. Luo, T. Yang, Clinical trial update on bispecific antibodies, antibody-drug conjugates, and antibody-containing regimens for acute lymphoblastic leukemia, J. Hematol. Oncol., 12 (2019), 1–13. http://dx.doi.org/10.1186/s13045-019-0703-z doi: 10.1186/s13045-019-0703-z
    [6] W. Liu, J. Ma, J. Chen, B. Huang, F. Liu, L. Li, et al., A novel TBK1/IKK$\epsilon$ is involved in immune response and interacts with MyD88 and MAVS in the scallop Chlamys farreri, Front. Immunol., 13 (2023), 1091419. http://dx.doi.org/10.3389/fimmu.2022.1091419 doi: 10.3389/fimmu.2022.1091419
    [7] J. N. Brudno, J. N. Kochenderfer, Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management, Blood Rev., 34 (2019), 45–55. http://dx.doi.org/10.1016/j.blre.2018.11.002 doi: 10.1016/j.blre.2018.11.002
    [8] C. Bailly, The potential value of amlexanox in the treatment of cancer: Molecular targets and therapeutic perspectives, Biochem. Pharmacol., 197 (2022), 114895. http://dx.doi.org/10.1016/j.bcp.2021.114895 doi: 10.1016/j.bcp.2021.114895
    [9] D. A. Berry, S. Zhou, H. Higley, L. Mukundan, S. Fu, G. H. Reaman, et al., Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: A meta-analysis, JAMA Oncol., 3 (2017), e170580. http://dx.doi.org/10.1001/jamaoncol.2017.0580 doi: 10.1001/jamaoncol.2017.0580
    [10] Q. A. Xiao, Q. He, L. Li, Y. Song, Y. R. Chen, J. Zeng, et al., Role of IKK$\varepsilon$ in the metabolic diseases: Physiology, pathophysiology, and pharmacology, Front. Pharmacol., 13 (2022), 888588. http://dx.doi.org/10.3389/fphar.2022.888588 doi: 10.3389/fphar.2022.888588
    [11] T. Liu, X. Gao, Y. Xin, Identification of an IKBKE inhibitor with antitumor activity in cancer cells overexpressing IKBKE, Cytokine, 116 (2019), 78–87. http://dx.doi.org/10.1016/j.cyto.2019.01.005 doi: 10.1016/j.cyto.2019.01.005
    [12] T. H. Tran, S. P. Hunger, The genomic landscape of pediatric acute lymphoblastic leukemia and precision medicine opportunities, Semin. Cancer Biol., 84 (2022), 144–152. http://dx.doi.org/10.1016/j.semcancer.2020.10.013 doi: 10.1016/j.semcancer.2020.10.013
    [13] J. P. Guo, S. K. Shu, L. He, Y. C. Lee, P. A. Kruk, S. Grenman, et al., Deregulation of IKBKE is associated with tumor progression, poor prognosis, and cisplatin resistance in ovarian cancer, Am. J. Pathol., 175 (2009), 324–333. http://dx.doi.org/10.2353/ajpath.2009.080767 doi: 10.2353/ajpath.2009.080767
    [14] T. S. Elton, H. Selemon, S. M. Elton, N. L. Parinandi, Regulation of the MIR155 host gene in physiological and pathological processes, Gene, 532 (2013), 1–12. http://dx.doi.org/10.1016/j.gene.2012.12.009 doi: 10.1016/j.gene.2012.12.009
    [15] H. J. Maier, T. G. Schips, A. Wietelmann, M. Krüger, C. Brunner, M. Sauter, et al., Cardiomyocyte-specific I$\kappa$B kinase (IKK)/NF-$\kappa$B activation induces reversible inflammatory cardiomyopathy and heart failure, Proc. Natl. Acad. Sci., 109 (2012), 11794–11799. http://dx.doi.org/10.1073/pnas.1116584109 doi: 10.1073/pnas.1116584109
    [16] M. Yin, X. Wang, J. Lu, Advances in IKBKE as a potential target for cancer therapy, Cancer Med., 9 (2019), 247–258. http://dx.doi.org/10.1002/cam4.2678 doi: 10.1002/cam4.2678
    [17] S. I. Göktuna, IKBKE-driven TPL2 and MEK1 phosphorylations sustain constitutive ERK1/2 activation in tumor cells, EXCLI J., 21 (2022), 436. https://www.excli.de/index.php/excli/article/view/4578
    [18] R. T. Bishop, S. Marino, D. de Ridder, R. J. Allen, D. V. Lefley, A. H. Sims, et al., Pharmacological inhibition of the IKK$\varepsilon$/TBK-1 axis potentiates the anti-tumour and anti-metastatic effects of docetaxel in mouse models of breast cancer, Cancer Lett., 450 (2019), 76–87. http://dx.doi.org/10.1016/j.canlet.2019.02.032 doi: 10.1016/j.canlet.2019.02.032
    [19] M. M. Uddin, B. Gaire, B. Deza, I. Vancurova, Interleukin-8-Induced Invasion Assay in Triple-Negative Breast Cancer Cells, Springer US, 2020. http://dx.doi.org/10.1007/978-1-0716-0247-8_9
    [20] M. Leonardi, E. Perna, S. Tronnolone, D. Colecchia, M. Chiariello, Activated kinase screening identifies the IKBKE oncogene as a positive regulator of autophagy, Autophagy, 15 (2018), 312–326. http://dx.doi.org/10.1080/15548627.2018.1517855 doi: 10.1080/15548627.2018.1517855
    [21] J. Guo, D. Kim, J. Gao, C. Kurtyka, H. Chen, C. Yu, et al., IKBKE is induced by STAT3 and tobacco carcinogen and determines chemosensitivity in non-small cell lung cancer, Oncogene, 32 (2012), 151–159. http://dx.doi.org/10.1038/onc.2012.39 doi: 10.1038/onc.2012.39
    [22] K. R. Balka, C. Louis, T. L. Saunders, A. M. Smith, D. J. Calleja, D. B. D'Silva, et al., TBK1 and IKK$\varepsilon$ act redundantly to mediate STING-induced NF-$\kappa$B responses in myeloid cells, Cell Rep., 31 (2020), 107492. http://dx.doi.org/10.1016/j.celrep.2020.03.056 doi: 10.1016/j.celrep.2020.03.056
    [23] S. Liu, A. E. Marneth, G. Alexe, S. R. Walker, H. I. Gandler, D. Q. Ye, et al., The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy, Blood Adv., 2 (2018), 3428–3442. http://dx.doi.org/10.1182/bloodadvances.2018016733 doi: 10.1182/bloodadvances.2018016733
    [24] J. Chen, X. Li, H. Liu, D. Zhong, K. Yin, Y. Li, et al., Bone marrow stromal cell-derived exosomal circular RNA improves diabetic foot ulcer wound healing by activating the nuclear factor erythroid 2-related factor 2 pathway and inhibiting ferroptosis, Diabet. Med., 40 (2023), e15031. http://dx.doi.org/10.1111/dme.15031 doi: 10.1111/dme.15031
    [25] S. Okada, K. Vaeteewoottacharn, R. Kariya, Application of highly immunocompromised mice for the establishment of patient-derived xenograft (PDX) models, Cells, 8 (2019), 889. http://dx.doi.org/10.3390/cells8080889 doi: 10.3390/cells8080889
    [26] A. Riemann, S. Reime, O. Thews, Acidic extracellular environment affects miRNA expression in tumors in vitro and in vivo, Int. J. Cancer, 144 (2018), 1609–1618. http://dx.doi.org/10.1002/ijc.31790 doi: 10.1002/ijc.31790
    [27] A. Bainbridge, S. Walker, J. Smith, K. Patterson, A. Dutt, Y. M. Ng, et al., IKBKE activity enhances AR levels in advanced prostate cancer via modulation of the Hippo pathway, Nucleic Acids Res., 48 (2020), 5366–5382. http://dx.doi.org/10.1093/nar/gkaa271 doi: 10.1093/nar/gkaa271
    [28] Y. Liu, J. Lu, Z. Zhang, L. Zhu, S. Dong, G. Guo, et al., Amlexanox, a selective inhibitor of IKBKE, generates anti-tumoral effects by disrupting the Hippo pathway in human glioblastoma cell lines, Cell Death Dis., 8 (2017), e3022–e3022. http://dx.doi.org/10.1038/cddis.2017.396 doi: 10.1038/cddis.2017.396
    [29] A. S. Duffield, C. G. Mullighan, M. J. Borowitz, International consensus classification of acute lymphoblastic leukemia/lymphoma, Virchows Arch., 482 (2022), 11–26. http://dx.doi.org/10.1007/s00428-022-03448-8 doi: 10.1007/s00428-022-03448-8
    [30] H. M. Kantarjian, D. J. DeAngelo, M. Stelljes, M. Liedtke, W. Stock, N. Gökbuget, et al., Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study, Cancer, 125 (2019), 2474–2487. http://dx.doi.org/10.1002/cncr.32116 doi: 10.1002/cncr.32116
    [31] C. Taştan, D. D. Kançağı, R. D. Turan, B. Yurtsever, D. undefinedakırsoy, S. Abanuz, et al., Preclinical assessment of efficacy and safety analysis of CAR-T cells (ISIKOK-19) targeting CD19-expressing b-cells for the first turkish academic clinical trial with relapsed/refractory ALL and NHL patients, Turk. J. Haematol., 37 (2020), 234–247. http://dx.doi.org/10.4274/tjh.galenos.2020.2020.0070 doi: 10.4274/tjh.galenos.2020.2020.0070
    [32] S. Challa, J. P. Guo, X. Ding, C. X. Xu, Y. Li, D. Kim, et al., IKBKE is a substrate of EGFR and a therapeutic target in non-small cell lung cancer with activating mutations of EGFR, Cancer Res., 76 (2016), 4418–4429. http://dx.doi.org/10.1158/0008-5472.CAN-16-0069 doi: 10.1158/0008-5472.CAN-16-0069
    [33] J. Cui, C. Wei, L. Deng, X. Kuang, Z. Zhang, C. Pierides, et al., MicroRNA-143 increases cell apoptosis in myelodysplastic syndrome through the Fas/FasL pathway both in-vitro and in-vivo, Int. J. Oncol., 53 (2018), 2191–2199. http://dx.doi.org/10.3892/ijo.2018.4534 doi: 10.3892/ijo.2018.4534
    [34] M. C. J. Bosman, J. J. Schuringa, W. J. Quax, E. Vellenga, Bortezomib sensitivity of acute myeloid leukemia CD34+ cells can be enhanced by targeting the persisting activity of NF-$\kappa$B and the accumulation of MCL-1, Exp. Hematol., 41 (2013), 530–538. http://dx.doi.org/10.1016/j.exphem.2013.02.002 doi: 10.1016/j.exphem.2013.02.002
    [35] D. Bauer, E. Mazzio, K. F. Soliman, Whole transcriptomic analysis of apigenin on TNF$\alpha$ immuno-activated MDA-MB-231 breast cancer cells, Cancer Genom, Proteomics, 16 (2019), 421–431. http://dx.doi.org/10.21873/cgp.20146 doi: 10.21873/cgp.20146
    [36] K. P. Seastedt, N. Pruett, C. D. Hoang, Mouse models for mesothelioma drug discovery and development, Expert Opin. Drug Discov., 16 (2020), 697–708. http://dx.doi.org/10.1080/17460441.2021.1867530 doi: 10.1080/17460441.2021.1867530
    [37] T. Liu, A. Li, Y. Xu, Y. Xin, MCCK1 enhances the anticancer effect of temozolomide in attenuating the invasion, migration and epithelial‐mesenchymal transition of glioblastoma cells in vitro and in vivo, Cancer Med., 8 (2019), 751–760. http://dx.doi.org/10.1002/cam4.1951 doi: 10.1002/cam4.1951
    [38] J. S. Boehm, J. J. Zhao, J. Yao, S. Y. Kim, R. Firestein, I. F. Dunn, et al., Integrative genomic approaches identify IKBKE as a breast cancer oncogene, Cell, 129 (2007), 1065–1079. http://dx.doi.org/10.1016/j.cell.2007.03.052 doi: 10.1016/j.cell.2007.03.052
    [39] R. J. Oldham, C. I. Mockridge, S. James, P. J. Duriez, H. T. C. Chan, K. L. Cox, et al., Fc$\gamma$RII (CD32) modulates antibody clearance in NOD SCID mice leading to impaired antibody-mediated tumor cell deletion, J. Immunother. Cancer, 8 (2020), e000619. http://dx.doi.org/10.1136/jitc-2020-000619 doi: 10.1136/jitc-2020-000619
    [40] Y. W. Lin, Z. M. Beharry, E. G. Hill, J. H. Song, W. Wang, Z. Xia, et al., A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma, Blood, 115 (2010), 824–833. http://dx.doi.org/10.1182/blood-2009-07-233445 doi: 10.1182/blood-2009-07-233445
    [41] J. Hwee, R. Sutradhar, J. C. Kwong, L. Sung, S. Cheng, J. D. Pole, Infections and the development of childhood acute lymphoblastic leukemia: a population-based study, Eur. J. Cancer Prev., 29 (2020), 538–545. http://dx.doi.org/10.1097/CEJ.0000000000000564 doi: 10.1097/CEJ.0000000000000564
    [42] M. W. Lato, A. Przysucha, S. Grosman, J. Zawitkowska, M. Lejman, The new therapeutic strategies in pediatric T-cell acute lymphoblastic leukemia, Int. J. Mol. Sci., 22 (2021), 4502. http://dx.doi.org/10.3390/ijms22094502 doi: 10.3390/ijms22094502
    [43] N. Safari-Alighiarloo, M. Taghizadeh, S. M. Tabatabaei, S. Namaki, M. Rezaei-Tavirani, Identification of common key genes and pathways between type 1 diabetes and multiple sclerosis using transcriptome and interactome analysis, Endocrine, 68 (2020), 81–92. http://dx.doi.org/10.1007/s12020-019-02181-8 doi: 10.1007/s12020-019-02181-8
    [44] W. Xie, S. Tian, J. Yang, S. Cai, S. Jin, T. Zhou, et al., OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity, Autophagy, 18 (2022), 2288–2302. http://dx.doi.org/10.1080/15548627.2022.2026098 doi: 10.1080/15548627.2022.2026098
    [45] J. Zhao, Y. Liu, L. Zhu, J. Li, Y. Liu, J. Luo, et al., Tumor cell membrane-coated continuous electrochemical sensor for GLUT1 inhibitor screening, J. Pharm. Anal., 13 (2023), 673–682. http://dx.doi.org/10.1016/j.jpha.2023.04.015 doi: 10.1016/j.jpha.2023.04.015
    [46] T. H. Nguyen-Vo, Q. H. Trinh, L. Nguyen, P. U. Nguyen-Hoang, T. N. Nguyen, D. T. Nguyen, et al., iCYP-MFE: Identifying human cytochrome P450 inhibitors using multitask learning and molecular fingerprint-embedded encoding, J. Chem. Inf. Model., 62 (2021), 5059–5068. http://dx.doi.org/10.1021/acs.jcim.1c00628 doi: 10.1021/acs.jcim.1c00628
    [47] Y. Zhu, R. Huang, Z. Wu, S. Song, L. Cheng, R. Zhu, Deep learning-based predictive identification of neural stem cell differentiation, Nat. Commun., 12 (2021), 2614. http://dx.doi.org/10.1038/s41467-021-22758-0 doi: 10.1038/s41467-021-22758-0
    [48] T. H. Nguyen-Vo, L. Nguyen, N. Do, P. H. Le, T. N. Nguyen, B. P. Nguyen, et al., Predicting drug-induced liver injury using convolutional neural network and molecular fingerprint-embedded features, ACS Omega, 5 (2020), 25432–25439. http://dx.doi.org/10.1021/acsomega.0c03866 doi: 10.1021/acsomega.0c03866
    [49] L. Nguyen, T. H. Nguyen Vo, Q. H. Trinh, B. H. Nguyen, P. U. Nguyen-Hoang, L. Le, et al., iANP-EC: Identifying anticancer natural products using ensemble learning incorporated with evolutionary computation, J. Chem. Inf. Model., 62 (2022), 5080–5089. http://dx.doi.org/10.1021/acs.jcim.1c00920 doi: 10.1021/acs.jcim.1c00920
    [50] T. H. Nguyen-Vo, Q. H. Trinh, L. Nguyen, T. T. T. Do, M. C. H. Chua, B. P. Nguyen, Predicting antimalarial activity in natural products using pretrained bidirectional encoder representations from transformers, J. Chem. Inf. Model., 62 (2021), 5050–5058. http://dx.doi.org/10.1021/acs.jcim.1c00584 doi: 10.1021/acs.jcim.1c00584
  • Reader Comments
  • © 2024 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(1088) PDF downloads(130) Cited by(0)

Article outline

Figures and Tables

Figures(4)  /  Tables(1)

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog