Upstream eventcell cycle, disrupted
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leading to testicular toxicity||adjacent||High||Moderate|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
Life Stage Applicability
|Not Otherwise Specified||High|
Key Event Relationship Description
Cell cycle dysregulation leads to apoptosis. microRNA-497, potentially targeting Bcl2 and Cyclin D2 (CCND2), induced apoptosis via the Bcl-2/Bax - caspase 9 - caspase 3 pathway and CCND2 protein in human umbilical vein endothelial cells (HUVECs) [Wu, 2016]. The microRNA-497 activated caspases 9 and 3, and decreased Bcl2 and CCND2 [Wu, 2016]. CCND2 is an important cell cycle gene that induces G1 arrest [Li, 2012], and deregulated CCND2 is implicated in cell proliferation inhibition [Wu, 2016, Mermelstein, 2005, Dong, 2010].
Evidence Supporting this KER
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, 1986]. Cell cycles characterized by the DNA content changes regulate cell death and cell proliferation [Lynch, 1986]. Cell gain and loss are balanced with mitosis and apoptosis [Cree, 1987]. Apoptosis is mediated by caspase activation [Porter, 1999]. Caspase-3 is activated in the programmed cell death, and the pathways to caspase-3 activation include caspase-9 and mitochondrial cytochrome c release [Porter, 1999]. The activation of caspase-3 leads to apoptotic chromatin condensation and DNA fragmentation [Porter, 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, 2017]. Sinularin induced caspases 8, 9, and 3, and pro-apoptotic protein Bax, whereas it decrease the anti-apoptotic Bcl-2 protein expression level [Chung, 2017].
- Cell cycle arrest such as G1 arrest and G1/S arrest are observed in apoptosis [Li, 2012, Dong, 2010].
- microRNA-1 and microRNA-206 represses CCND2, while microRNA-29 represses CCND2 and induces G1 arrest and apoptosis in rhabdomyosarcoma [Li, 2012].
- The treatment with HDAC inhibitor, methoxyacetic acid (MAA) in prostate cancer cells induced growth arrest and apoptosis [Parajuli, 2014]. MAA blocks G1/S transition of cell cycle [Parajuli, 2014]. MAA reduces CDK4 and CDK2, and decreases protein expression of BIRC2 and activates caspase 7 and 3 [Parajuli, 2014].
Uncertainties and Inconsistencies
MAA induces apoptosis, however, the MAA-induced changes of BCL2, BAX, BCL2L1, BAD, BID, MCL1, and CFLAR, pro-apoptotic and anti-apoptotic genes were not observed [Parajuli, 2014]. microRNA-497 induce activation of caspase-9 and -3, followed by apoptosis, however, the caspase-9 and -3 protein levels were repressed by the ectopic expression of microRNA-497, which remains uncertain [Wu, 2016].
Quantitative Understanding of the Linkage
MAA (5 mM) decreases CDK4, CDK2 expression in 48 hrs after the treatment, which indicates the G1 arrest [Parajuli, 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, 2014].
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationship between disrupted cell cycle and apoptosis is likely well conserved between species.
- MicroRNA let-7a induced cell cycle arrest, inhibited CCND2 and proliferation of human prostate cancer cells (Homo sapiens) [Dong, 2010].
- microRNA-497 down-regulated CCND2 and induced apoptosis via the Bcl-2/Bax-caspase 9- caspase 3 pathway in HUVECs (Homo sapiens) [Wu, 2016].
- micoRNA-26a regulated p53-mediated apoptosis and CCND2 and CCNE2 in mouse hepatocyte (Mus musculus) [Zhou, 2016].
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
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
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
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 JFR et al. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239-257
Sarraf CE and Bowen ID (1986) Kinetic studies on a murine sarcoma and an analysis of apoptosis. Br J Cancer 54: 989-998
Lynch MP 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
Cree IA et al. (1987) Cell death in granulomata: the role of apoptosis J Clin Pathol 40: 1314-1319
Porter AG and Janicke RU. (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6: 99-104
Chung TW et al. (2017) Sinularin induces DNA damage, G2/M phase arrest, and apoptosis in human hepatocellular carcinoma cells. BMC Complement Altern Med 17: 62
Parajuli KR et al. (2014) Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis. Am J Clin Exp Urol 2:300-313
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