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Cell cycle, disrupted leads to Apoptosis
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Histone deacetylase inhibition leading to testicular atrophy||adjacent||Moderate||Moderate||Brendan Ferreri-Hanberry (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|Not Otherwise Specified||High|
Key Event Relationship Description
Cell cycle dysregulation may lead to apoptosis. Cell cycles characterized by the DNA content changes regulate cell death and cell proliferation [Lynch et al., 1986].
Evidence Collection Strategy
Evidence Supporting this KER
The microRNA-497, potentially targeting Bcl-2 and cyclin D2 (CCND2), activated caspases 9/3, and induced apoptosis via the Bcl-2/Bax - caspase 9 - caspase 3 pathway and CCND2 protein in human umbilical vein endothelial cells (HUVECs) [Wu, 2016]. CCND2 is an important cell cycle gene, of which a decrease in expression induces G1 arrest [Li et al., 2012], and dysregulated CCND2 is implicated in cell proliferation inhibition [Wu et al., 2016; Mermelstein et al., 2005; Dong et al., 2010].
The incidence of apoptosis was increased in vincristine-treated cells, in which metaphases were arrested, compared to untreated cells, which indicates that cell cycle dysregulation leads to apoptosis [Sarraf and Bowen, 1986]. Cell gain and loss are balanced with mitosis and apoptosis [Cree et al., 1987]. Apoptosis is mediated by caspase activation [Porter and Janicke, 1999]. Caspase-3 is activated in programmed cell death, and the pathways to caspase-3 activation include caspase-9 and mitochondrial cytochrome c release [Porter and Janicke, 1999]. The activation of caspase-3 leads to apoptotic chromatin condensation and DNA fragmentation [Porter and Janicke, 1999]. Sinularin, a marine natural compound, exhibited DNA damage and induced G2/M cell cycle arrest, followed by apoptosis in human hepatocellular carcinoma HepG2 cells [Chung et al., 2017]. Sinularin induced caspases 8, 9, and 3, and pro-apoptotic protein Bax, whereas it decreases the anti-apoptotic Bcl-2 protein expression level [Chung et al., 2017].
- Cell cycle arrests such as G1 arrest and G1/S arrest are observed in apoptosis [Li et al., 2012; Dong et al., 2010].
- microRNA-1 and microRNA-206 repress CCND2, while microRNA-29 represses CCND2 and induces G1 arrest and apoptosis in rhabdomyosarcoma [Li et al., 2012].
- The blockade of G1/S transition of cell cycle and reduction of CDK4 and CDK2, and apoptosis have occurred in HDAC inhibitor treatment [Parajuli et al., 2014].
Uncertainties and Inconsistencies
MAA induces CDK4 and CDK2 decreases, cell cycle arrest, and apoptosis, which may be regulated by several pathways [Parajuli et al., 2014].
Known modulating factors
Quantitative Understanding of the Linkage
Cell proliferation which was determined at daily intervals after a 24-hr pulse of [3H]thymidine changed as the amount of DNA in the cultures changed. Cell death which was measured by lactic dehydrogenase (LDH) activity in the medium changed in parallel with the changes in cell proliferation [Lynch et al., 1986].
Treatment with sinularin, a natural product isolated from cultured soft coral possessing antineoplastic activity, at 12.5, 25, 50 microM resulted in cell cycle disruption and apoptosis in a dose-dependent manner in hepatocellular carcinoma cells [Chun et al., 2017]. The cell cycle disruption and apoptosis are induced by 30 microM curcumin, a major component extracted from turmeric plants that have an anti-cancer effect [Liu et al., 2018].
MAA (5 mM) decreases CDK4, CDK2 expression 48 hrs after the treatment, which indicates the G1 arrest [Parajuli et al., 2014]. MAA (5 mM) decreases the protein expression of procaspase 7 and 3 in 24 to 72 hrs after the treatment, indicating the activation of caspases 7 and 3 [Parajuli et al., 2014].
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationship between disrupted cell cycle and apoptosis is likely well conserved between species. The examples are only given for mammals:
- MicroRNA let-7a induced cell cycle arrest and inhibited CCND2 and proliferation of human prostate cancer cells (Homo sapiens) [Dong et al., 2010].
- The microRNA-497 down-regulated CCND2 and induced apoptosis via the Bcl-2/Bax-caspase 9- caspase 3 pathway in HUVECs (Homo sapiens) [Wu et al., 2016].
- The microRNA-26a regulated p53-mediated apoptosis and CCND2 and CCNE2 in mouse hepatocyte (Mus musculus) [Zhou et al., 2016].
Chung, T.W. et al. (2017), "Sinularin induces DNA damage, G2/M phase arrest, and apoptosis in human hepatocellular carcinoma cells", BMC Complement Altern Med 17:62
Cree, I.A. et al. (1987), "Cell death in granulomata: the role of apoptosis", J Clin Pathol 40:1314-1319
Dong, Q. et al. (2010), "microRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2", PLoS One 5:e10147
Kerr, J.F.R. et al. (1972), "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics", Br J Cancer 26:239-257
Li, L. et al. (2012), "Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma", Lab Invest 92:571-583
Liu, W. et al. (2018), "Curcumin suppresses gastric cancer biological activity by regulation of miRNA-21: an in vitro study", Int J Clin Exp Pathol 11:5820-5289
Lynch, M.P. et al. (1986), "Evidence for soluble factors regulating cell death and cell proliferation in primary cultures of rabbit endometrial cells grown on collagen", Proc Natl Acad Sci USA 83:4784-4788
Mermelshtein, A. et al. (2005), "Expression of F-type cyclins in colon cancer and in cell lines from colon carcinomas", Br J Cancer 93:338-345
Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-313
Porter, A.G. and Janicke, R.U. (1999), "Emerging roles of caspase-3 in apoptosis", Cell Death Differ 6:99-104
Sarraf, C.E. and Bowen, I.D. (1986), "Kinetic studies on a murine sarcoma and an analysis of apoptosis", Br J Cancer 54:989-998
Wu, R. et al. (2016), "microRNA-497 induces apoptosis and suppressed proliferation via the Bcl-2/Bax-caspase9-caspase 3 pathway and cyclin D2 protein in HUVECs", PLoS One 11:e0167052
Zhou, J. et al. (2016), "miR-26a regulates mouse hepatocyte proliferation via directly targeting the 3’ untranslated region of CCND2 and CCNE2", Hepatobiliary Pancreat Dis Int 15:65-72