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Current Cancer Drug Targets


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

Research Article

CDK-associated Cullin 1 Promotes Cell Proliferation and Inhibits Cell Apoptosis in Human Glioblastoma

Author(s): Xiaohua Zhang, Tianying Zhang, Xiaojuan Han, Zhongying Qiu, Jianghong Cheng, Xingchun Gao and Xingchun Gou*

Volume 21, Issue 10, 2021

Published on: 02 June, 2021

Page: [870 - 880] Pages: 11

DOI: 10.2174/1568009621666210602164225

Price: $65


Background: Glioma is the most common intracranial primary tumour of adult humans, and its pathological mechanism and molecular characteristics are still under investigation. CDK-associated cullin 1 (CACUL1) has been shown to regulate colorectal carcinoma, lung cancer, and gastric cancer development.

Objective: This study aims to explore the role of CACUL1 in the pathogenesis of human glioma.

Methods: CACUL1 levels in human glioma tissue microarrays were detected by immunohistochemistry analysis. Two glioblastoma cell lines, namely, U87 and U251, were transfected with CACUL1 siRNA, and cell proliferation, cell cycle, cell apoptosis, and regulating molecules, including cyclinE1, cyclinA2, CDK2, p21, Bcl2, and Bax were assessed by CCK8, flow cytometry, and Western blot.

Results: CACUL1 expression in glioma tissue was significantly higher than that in normal brain tissue. CACUL1 knockdown impeded cell proliferation, induced cell apoptosis, and caused G1/S transition arrest in glioblastoma cells. The cell cycle-related proteins CDK2, cyclinE1, and cyclinA2 were dramatically decreased in the CACUL1 siRNA group compared to the non-targeting siRNA group in both U87 and U251 cells, while the CDK inhibitory protein p21 was increased in U87 cells. Additionally, the Bcl-2/Bax ratio was significantly decreased.

Conclusion: CACUL1 can promote cell proliferation and suppress apoptosis of glioma cells and might serve as a potential oncogene for gliomas.

Keywords: CACUL1, glioma, proliferation, apoptosis, CDK2, cell cycle.

Graphical Abstract
Chertok, B.; David, A.E.; Yang, V.C. Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration. Biomaterials, 2010, 31(24), 6317-6324.
[] [PMID: 20494439]
Jain, A.; Betancur, M.; Patel, G.D.; Valmikinathan, C.M.; Mukhatyar, V.J.; Vakharia, A.; Pai, S.B.; Brahma, B.; MacDonald, T.J.; Bellamkonda, R.V. Guiding intracortical brain tumour cells to an extracortical cytotoxic hydrogel using aligned polymeric nanofibres. Nat. Mater., 2014, 13(3), 308-316.
[] [PMID: 24531400]
Ostrom, Q.T.; Gittleman, H.; Truitt, G.; Boscia, A.; Kruchko, C.; Barnholtz-Sloan, J.S. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the united states in 2011-2015. Neuro Oncol, 2018, 20(suppl_4), iv1-iv86.
[] [PMID: 30445539]
Bilmin, K.; Kujawska, T.; Grieb, P. Sonodynamic therapy for gliomas. Perspectives and Prospects of Selective Sonosensitization of Glioma Cells, 2019, 8.
Gusyatiner, O.; Hegi, M.E. Glioma epigenetics: From subclassification to novel treatment options. Semin. Cancer Biol., 2018, 51, 50-58.
[] [PMID: 29170066]
Kong, Y.; Nan, K.; Yin, Y. Identification and characterization of CAC1 as a novel CDK2-associated cullin. Cell Cycle, 2009, 8(21), 3552-3561.
[] [PMID: 19829063]
Chen, T.J.; Gao, F.; Yang, T.; Thakur, A.; Ren, H.; Li, Y.; Zhang, S.; Wang, T.; Chen, M.W. CDK-associated Cullin 1 promotes cell proliferation with activation of ERK1/2 in human lung cancer A549 cells. Biochem. Biophys. Res. Commun., 2013, 437(1), 108-113.
[] [PMID: 23806693]
Zheng, Q.; Zhao, L.Y.; Kong, Y.; Nan, K.J.; Yao, Y.; Liao, Z.J. CDK-associated Cullin 1 can promote cell proliferation and inhibit cisplatin-induced apoptosis in the AGS gastric cancer cell line. World J. Surg. Oncol., 2013, 11, 5.
[] [PMID: 23311997]
Kong, Y.; Bai, P.S.; Sun, H.; Nan, K.J. Expression of the newly identified gene CAC1 in the hippocampus of Alzheimer’s disease patients. J. Mol. Neurosci., 2012, 47(2), 207-218.
[] [PMID: 22415352]
Schenk, R.L.; Strasser, A.; Dewson, G. BCL-2: Long and winding path from discovery to therapeutic target. Biochem. Biophys. Res. Commun., 2017, 482(3), 459-469.
[] [PMID: 28212732]
Huang, R.; Qian, D.; Hu, M.; Zhang, X.; Song, J.; Li, L.; Chen, H.; Wang, B. Association between human cytomegalovirus infection and histone acetylation level in various histological types of glioma. Oncol. Lett., 2015, 10(5), 2812-2820.
[] [PMID: 26722247]
Sarikas, A.; Hartmann, T.; Pan, Z.Q. The cullin protein family. Genome Biol., 2011, 12(4), 220.
[] [PMID: 21554755]
Lee, J.; Zhou, P. Cullins and cancer. Genes Cancer, 2010, 1(7), 690-699.
[] [PMID: 21127736]
Hochegger, H.; Takeda, S.; Hunt, T. Cyclin-dependent kinases and cell-cycle transitions: Does one fit all? Nat. Rev. Mol. Cell Biol., 2008, 9(11), 910-916.
[] [PMID: 18813291]
el-Deiry, W.S.; Tokino, T.; Velculescu, V.E.; Levy, D.B.; Parsons, R.; Trent, J.M.; Lin, D.; Mercer, W.E.; Kinzler, K.W.; Vogelstein, B. WAF1, a potential mediator of p53 tumor suppression. Cell, 1993, 75(4), 817-825.
[] [PMID: 8242752]
Owens, D.M.; Keyse, S.M. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene, 2007, 26(22), 3203-3213.
[] [PMID: 17496916]
Abbas, T.; Dutta, A. p21 in cancer: Intricate networks and multiple activities. Nat. Rev. Cancer, 2009, 9(6), 400-414.
[] [PMID: 19440234]
Viale, A.; De Franco, F.; Orleth, A.; Cambiaghi, V.; Giuliani, V.; Bossi, D.; Ronchini, C.; Ronzoni, S.; Muradore, I.; Monestiroli, S.; Gobbi, A.; Alcalay, M.; Minucci, S.; Pelicci, P.G. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature, 2009, 457(7225), 51-56.
[] [PMID: 19122635]
Ishii, N.; Maier, D.; Merlo, A.; Tada, M.; Sawamura, Y.; Diserens, A.C.; Van Meir, E.G. Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol., 1999, 9(3), 469-479.
[] [PMID: 10416987]
Yip, K.W.; Reed, J.C. Bcl-2 family proteins and cancer. Oncogene, 2008, 27(50), 6398-6406.
[] [PMID: 18955968]
Mohan, S.; Abdelwahab, S.I.; Kamalidehghan, B.; Syam, S.; May, K.S.; Harmal, N.S.; Shafifiyaz, N.; Hadi, A.H.; Hashim, N.M.; Rahmani, M.; Taha, M.M.; Cheah, S.C.; Zajmi, A. Involvement of NF-κB and Bcl2/Bax signaling pathways in the apoptosis of MCF7 cells induced by a xanthone compound Pyranocycloartobiloxanthone A. Phytomedicine, 2012, 19(11), 1007-1015.
[] [PMID: 22739412]
Vucicevic, K.; Jakovljevic, V.; Colovic, N.; Tosic, N.; Kostic, T.; Glumac, I.; Pavlovic, S.; Karan-Djurasevic, T.; Colovic, M. Association of Bax expression and Bcl2/Bax ratio with clinical and molecular prognostic markers in chronic lymphocytic leukemia. J. Med. Biochem., 2016, 35(2), 150-157.
[] [PMID: 28356875]
Tsujimoto, Y. Role of Bcl-2 family proteins in apoptosis: Apoptosomes or mitochondria? Genes Cells, 1998, 3(11), 697-707.
[] [PMID: 9990505]

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