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Cancer Cell International
Published in: Cancer Cell International 1/2021

01-12-2021 | Glioblastoma | Review

The dysregulated expression and functional effect of CaMK2 in cancer

Authors: Qi He, Zhenyu Li

Published in: Cancer Cell International | Issue 1/2021

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Abstract

CaMK2 (calcium/calmodulin-dependent protein kinase 2), a multifunctional serine/threonine-protein kinase involved in diverse cellular processes, is vital for the transduction of the Ca2+ signaling cascade. Recently, research has highlighted the involvement of CaMK2 in cancer development. However, the specific effects of CaMK2 on cancer have not been fully elucidated. In this review, we summarize not only the altered expression of CaMK2 in a range of cancers, as evidenced by bioinformatics analysis, but also the significant role of CaMK2 in regulating cancer progression, such as proliferation and metastasis. In addition, we described the functional influence of CaMK2 on cancer stemness and resistance. Understanding the critical effects and mechanisms of CaMK2 in cancer would facilitate the development of a promising therapeutic strategy for cancer treatment.
Literature
1.
Hudmon A, Schulman H. Neuronal Ca2+/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function. Annu Rev Biochem. 2002;71:473–510.PubMedCrossRef
2.
Shonesy BC, et al. CaMKII: a molecular substrate for synaptic plasticity and memory. Prog Mol Biol Transl Sci. 2014;122:61–87.PubMedCrossRef
3.
Skelding KA, Rostas JA, Verrills NM. Controlling the cell cycle: the role of calcium/calmodulin-stimulated protein kinases I and II. Cell Cycle. 2011;10(4):631–9.PubMedCrossRef
4.
Braun AP, Schulman H. The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. Annu Rev Physiol. 1995;57:417–45.PubMedCrossRef
5.
Brzozowski JS, Skelding KA. The multi-functional calcium/calmodulin stimulated protein kinase (CaMK) family: emerging targets for anti-cancer therapeutic intervention. Pharmaceuticals (Basel). 2019;12(1):8.CrossRef
6.
Fong YL, et al. Studies of the regulatory mechanism of Ca2+/calmodulin-dependent protein kinase II. Mutation of threonine 286 to alanine and aspartate. J Biol Chem. 1989;264(28):16759–63.PubMedCrossRef
7.
Meyer T, et al. Calmodulin trapping by calcium-calmodulin-dependent protein kinase. Science. 1992;256(5060):1199–202.PubMedCrossRef
8.
Skelding KA, Rostas JA. Regulation of CaMKII in vivo: the importance of targeting and the intracellular microenvironment. Neurochem Res. 2009;34(10):1792–804.PubMedCrossRef
9.
10.
11.
12.
Schworer CM, Colbran RJ, Soderling TR. Reversible generation of a Ca2+-independent form of Ca2+(calmodulin)-dependent protein kinase II by an autophosphorylation mechanism. J Biol Chem. 1986;261(19):8581–4.PubMedCrossRef
13.
14.
15.
Coultrap SJ, Bayer KU. Nitric oxide induces Ca2+-independent activity of the Ca2+/calmodulin-dependent protein kinase II (CaMKII). J Biol Chem. 2014;289(28):19458–65.PubMedPubMedCentralCrossRef
16.
Ducibella T, Schultz RM, Ozil JP. Role of calcium signals in early development. Semin Cell Dev Biol. 2006;17(2):324–32.PubMedCrossRef
17.
Zayzafoon M. Calcium/calmodulin signaling controls osteoblast growth and differentiation. J Cell Biochem. 2006;97(1):56–70.PubMedCrossRef
18.
Wang C, et al. A novel endogenous human CaMKII inhibitory protein suppresses tumor growth by inducing cell cycle arrest via p27 stabilization. J Biol Chem. 2008;283(17):11565–74.PubMedPubMedCentralCrossRef
19.
Ma S, et al. Endogenous human CaMKII inhibitory protein suppresses tumor growth by inducing cell cycle arrest and apoptosis through down-regulation of the phosphatidylinositide 3-kinase/Akt/HDM2 pathway. J Biol Chem. 2009;284(37):24773–82.PubMedPubMedCentralCrossRef
20.
Giese KP, et al. Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science. 1998;279(5352):870–3.PubMedCrossRef
21.
Miller S, et al. Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron. 2002;36(3):507–19.PubMedCrossRef
22.
Mercure MZ, Ginnan R, Singer HA. CaM kinase II delta2-dependent regulation of vascular smooth muscle cell polarization and migration. Am J Physiol Cell Physiol. 2008;294(6):C1465–75.PubMedCrossRef
23.
Cohen MB, Rokhlin OW. Mechanisms of prostate cancer cell survival after inhibition of AR expression. J Cell Biochem. 2009;106(3):363–71.PubMedCrossRef
24.
Nitzki F, et al. Tumor stroma-derived Wnt5a induces differentiation of basal cell carcinoma of Ptch-mutant mice via CaMKII. Cancer Res. 2010;70(7):2739–48.PubMedCrossRef
25.
Minami H, Inoue S, Hidaka H. The effect of KN-62, Ca2+/calmodulin dependent protein kinase II inhibitor on cell cycle. Biochem Biophys Res Commun. 1994;199(1):241–8.PubMedCrossRef
26.
Tombes RM, et al. G1 cell cycle arrest and apoptosis are induced in NIH 3T3 cells by KN-93, an inhibitor of CaMK-II (the multifunctional Ca2+/CaM kinase). Cell Growth Differ. 1995;6(9):1063–70.PubMed
27.
Hennig EE, et al. Comparative kinome analysis to identify putative colon tumor biomarkers. J Mol Med (Berl). 2012;90(4):447–56.CrossRef
28.
Feng YY, et al. Alteration of microRNA-4474/4717 expression and CREB-binding protein in human colorectal cancer tissues infected with Fusobacterium nucleatum. PLoS ONE. 2019;14(4):e0215088.PubMedPubMedCentralCrossRef
29.
Li JN, et al. Differences in gene expression profiles and carcinogenesis pathways between colon and rectal cancer. J Dig Dis. 2012;13(1):24–32.PubMedCrossRef
30.
Johansson FK, Goransson H, Westermark B. Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice. Oncogene. 2005;24(24):3896–905.PubMedCrossRef
31.
Xiong DD, et al. In silico analysis identified miRNAbased therapeutic agents against glioblastoma multiforme. Oncol Rep. 2019;41(4):2194–208.PubMedPubMedCentral
32.
van den Boom J, et al. Characterization of gene expression profiles associated with glioma progression using oligonucleotide-based microarray analysis and real-time reverse transcription-polymerase chain reaction. Am J Pathol. 2003;163(3):1033–43.PubMedPubMedCentralCrossRef
33.
Zhang Y, Xu J, Zhu X. A 63 signature genes prediction system is effective for glioblastoma prognosis. Int J Mol Med. 2018;41(4):2070–8.PubMedPubMedCentral
34.
Lian M, et al. Microarray gene expression analysis of chemosensitivity for docetaxel, cisplatin and 5-fluorouracil (TPF) combined chemotherapeutic regimen in hypopharyngeal squamous cell carcinoma. Chin J Cancer Res. 2017;29(3):204–12.PubMedPubMedCentralCrossRef
35.
Shao B, et al. Plasma CAMK2A predicts chemotherapy resistance in metastatic triple negative breast cancer. Int J Clin Exp Pathol. 2018;11(2):650–63.PubMedPubMedCentral
36.
Tang S, et al. Genome-wide association study of survival in early-stage non-small cell lung cancer. Ann Surg Oncol. 2015;22(2):630–5.PubMedCrossRef
37.
Kim JH, Kim TW, Kim SJ. Downregulation of ARFGEF1 and CAMK2B by promoter hypermethylation in breast cancer cells. BMB Rep. 2011;44(8):523–8.PubMedCrossRef
38.
39.
Wang Z, et al. RNA sequencing of esophageal adenocarcinomas identifies novel fusion transcripts, including NPC1-MELK, arising from a complex chromosomal rearrangement. Cancer. 2017;123(20):3916–24.PubMedCrossRef
40.
Jing Z, et al. SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIgamma/AKT-mediated pathway. Cancer Lett. 2016;372(2):226–38.PubMedPubMedCentralCrossRef
41.
Chen W, et al. Ca(2+)/calmodulin-dependent protein kinase II regulates colon cancer proliferation and migration via ERK1/2 and p38 pathways. World J Gastroenterol. 2017;23(33):6111–8.PubMedPubMedCentralCrossRef
42.
Britschgi A, et al. Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling. Proc Natl Acad Sci USA. 2013;110(11):E1026–34.PubMedPubMedCentralCrossRef
43.
Chi M, et al. Phosphorylation of calcium/calmodulin-stimulated protein kinase II at T286 enhances invasion and migration of human breast cancer cells. Sci Rep. 2016;6:33132.PubMedPubMedCentralCrossRef
44.
Hoffman A, et al. Dephosphorylation of CaMKII at T253 controls the metaphase–anaphase transition. Cell Signal. 2014;26(4):748–56.PubMedCrossRef
45.
Liu Z, et al. Calcium/calmodulindependent protein kinase II enhances metastasis of human gastric cancer by upregulating nuclear factorkappaB and Aktmediated matrix metalloproteinase9 production. Mol Med Rep. 2014;10(5):2459–64.PubMedCrossRef
46.
Dai L, et al. DAG/PKCdelta and IP3/Ca(2)(+)/CaMK IIbeta operate in parallel to each other in PLCgamma1-driven cell proliferation and migration of human gastric adenocarcinoma cells, through Akt/mTOR/S6 pathway. Int J Mol Sci. 2015;16(12):28510–22.PubMedPubMedCentralCrossRef
47.
Lee KH. CaMKII Inhibitor KN-62 Blunts tumor response to Hypoxia by inhibiting HIF-1alpha in hepatoma cells. Korean J Physiol Pharmacol. 2010;14(5):331–6.PubMedPubMedCentralCrossRef
48.
Meng Z, et al. Berbamine inhibits the growth of liver cancer cells and cancer-initiating cells by targeting Ca(2)(+)/calmodulin-dependent protein kinase II. Mol Cancer Ther. 2013;12(10):2067–77.PubMedCrossRef
49.
Mamaeva OA, et al. Calcium/calmodulin-dependent kinase II regulates notch-1 signaling in prostate cancer cells. J Cell Biochem. 2009;106(1):25–32.PubMedCrossRef
50.
Rokhlin OW, et al. Calcium/calmodulin-dependent kinase II plays an important role in prostate cancer cell survival. Cancer Biol Ther. 2007;6(5):732–42.PubMedCrossRef
51.
Yu G, et al. Organelle-derived Acetyl-CoA promotes prostate cancer cell survival, migration, and metastasis via activation of calmodulin kinase II. Cancer Res. 2018;78(10):2490–502.PubMedPubMedCentralCrossRef
52.
Rokhlin OW, et al. KN-93 inhibits androgen receptor activity and induces cell death irrespective of p53 and Akt status in prostate cancer. Cancer Biol Ther. 2010;9(3):224–35.PubMedCrossRef
53.
Wang Q, Huang L, Yue J. Oxidative stress activates the TRPM2-Ca(2+)-CaMKII-ROS signaling loop to induce cell death in cancer cells. Biochim Biophys Acta Mol Cell Res. 2017;1864(6):957–67.PubMedCrossRef
54.
55.
56.
Si J, Collins SJ. Activated Ca2+/calmodulin-dependent protein kinase II gamma is a critical regulator of myeloid leukemia cell proliferation. Cancer Res. 2008;68(10):3733–42.PubMedPubMedCentralCrossRef
57.
Gu Y, et al. CaMKII gamma, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine. Blood. 2012;120(24):4829–39.PubMedPubMedCentralCrossRef
58.
59.
60.
John S, Sivakumar KC, Mishra R. Bacoside a induces tumor cell death in human glioblastoma cell lines through catastrophic macropinocytosis. Front Mol Neurosci. 2017;10:171.PubMedPubMedCentralCrossRef
61.
Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717–28.PubMedCrossRef
62.
Clarke MF, et al. Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66(19):9339–44.PubMedCrossRef
63.
64.
65.
Meng Z, et al. CAMK2gamma antagonizes mTORC1 activation during hepatocarcinogenesis. Oncogene. 2017;36(17):2446–56.PubMedCrossRef
66.
Shin HJ, Lee S, Jung HJ. A curcumin derivative hydrazinobenzoylcurcumin suppresses stem-like features of glioblastoma cells by targeting Ca(2+)/calmodulin-dependent protein kinase II. J Cell Biochem. 2019;120(4):6741–52.PubMedCrossRef
67.
68.
Park KC, et al. Survival of cancer stem-like cells under metabolic stress via CaMK2alpha-mediated upregulation of sarco/endoplasmic reticulum calcium ATPase expression. Clin Cancer Res. 2018;24(7):1677–90.PubMedCrossRef
69.
Chai S, et al. Ca2+/calmodulin-dependent protein kinase IIgamma enhances stem-like traits and tumorigenicity of lung cancer cells. Oncotarget. 2015;6(18):16069–83.PubMedPubMedCentralCrossRef
70.
Riganti C, et al. Artemisinin induces doxorubicin resistance in human colon cancer cells via calcium-dependent activation of HIF-1alpha and P-glycoprotein overexpression. Br J Pharmacol. 2009;156(7):1054–66.PubMedPubMedCentralCrossRef
71.
Liu S, et al. c-Jun and Camk2a contribute to the drug resistance of induction docetaxel/cisplatin/5-fluorouracil in hypopharyngeal carcinoma. Int J Clin Exp Pathol. 2018;11(9):4605–13.PubMedPubMedCentral
72.
Xu X, et al. Overexpression of SMARCA2 or CAMK2D is associated with cisplatin resistance in human epithelial ovarian cancer. Oncol Lett. 2018;16(3):3796–804.PubMedPubMedCentral
73.
Metadata
Title
The dysregulated expression and functional effect of CaMK2 in cancer
Authors
Qi He
Zhenyu Li
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-02030-7

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