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E2F1-dependent pathways are involved in amonafide analogue 7-d-induced DNA damage, G2/M arrest, and apoptosis in p53-deficient K562 cells.
J Cell Biochem. 2012 Oct; 113(10):3165-77.JC

Abstract

The E2F1 gene well known is its pivotal role in regulating the entry from G1 to S phase, while the salvage antitumoral pathway which implicates it, especially in the absence of p53, is not fully characterized. We therefore attempted to identify the up- and down-stream events involved in the activation of the E2F1-dependent pro-apoptotic pathway. For this purpose, a amonafide analogue, 7-d (2-(3-(2-(Dimethylamino)ethylamino)propyl)-6-(dodecylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione) was screened, which exhibited high antitumor activity against p53-deficient human Chronic Myelogenous Leukemia (CML) K562 cells. Analysis of flow cytometry and western blots of K562 cells treated with 7-d revealed an appreciable G2/M cycle arrest and apoptosis in a dose and time-dependent manner via p53-independent pathway. A striking increase in "Comet tail" formation and γ-H2AX expression showed that DNA double strand breaks (DSB) were caused by 7-d treatment. ATM/ATR signaling was reported to connect E2F1 induction with apoptosis in response to DNA damage. Indeed, 7-d-induced G2/M arrest and apoptosis were antagonized by ATM/ATR signaling inhibitor, Caffeine, which suggested that ATM/ATR signaling was activated by 7-d treatment. Furthermore, the increased expression of E2F1, p73, and Apaf-1 and p73 dissociation from HDM2 was induced by 7-d treatment, however, knockout of E2F1 expression reversed p73, Apaf-1, and p21(Cip1/WAF1) expression, reactivated cell cycle progression, and inhibited 7-d-induced apoptosis. Altogether our results for the first time indicate that 7-d mediates its growth inhibitory effects on CML p53-deficient cells via the activation of an E2F1-dependent mitochondrial and cell cycle checkpoint signaling pathway which subsequently targets p73, Apaf-1, and p21(Cip1/WAF1).

Authors+Show Affiliations

State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237, PR China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22593008

Citation

Li, Yiquan, et al. "E2F1-dependent Pathways Are Involved in Amonafide Analogue 7-d-induced DNA Damage, G2/M Arrest, and Apoptosis in P53-deficient K562 Cells." Journal of Cellular Biochemistry, vol. 113, no. 10, 2012, pp. 3165-77.
Li Y, Shao J, Shen K, et al. E2F1-dependent pathways are involved in amonafide analogue 7-d-induced DNA damage, G2/M arrest, and apoptosis in p53-deficient K562 cells. J Cell Biochem. 2012;113(10):3165-77.
Li, Y., Shao, J., Shen, K., Xu, Y., Liu, J., & Qian, X. (2012). E2F1-dependent pathways are involved in amonafide analogue 7-d-induced DNA damage, G2/M arrest, and apoptosis in p53-deficient K562 cells. Journal of Cellular Biochemistry, 113(10), 3165-77. https://doi.org/10.1002/jcb.24194
Li Y, et al. E2F1-dependent Pathways Are Involved in Amonafide Analogue 7-d-induced DNA Damage, G2/M Arrest, and Apoptosis in P53-deficient K562 Cells. J Cell Biochem. 2012;113(10):3165-77. PubMed PMID: 22593008.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - E2F1-dependent pathways are involved in amonafide analogue 7-d-induced DNA damage, G2/M arrest, and apoptosis in p53-deficient K562 cells. AU - Li,Yiquan, AU - Shao,Jin, AU - Shen,Ke, AU - Xu,Yufang, AU - Liu,Jianwen, AU - Qian,Xuhong, PY - 2012/5/18/entrez PY - 2012/5/18/pubmed PY - 2013/1/8/medline SP - 3165 EP - 77 JF - Journal of cellular biochemistry JO - J Cell Biochem VL - 113 IS - 10 N2 - The E2F1 gene well known is its pivotal role in regulating the entry from G1 to S phase, while the salvage antitumoral pathway which implicates it, especially in the absence of p53, is not fully characterized. We therefore attempted to identify the up- and down-stream events involved in the activation of the E2F1-dependent pro-apoptotic pathway. For this purpose, a amonafide analogue, 7-d (2-(3-(2-(Dimethylamino)ethylamino)propyl)-6-(dodecylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione) was screened, which exhibited high antitumor activity against p53-deficient human Chronic Myelogenous Leukemia (CML) K562 cells. Analysis of flow cytometry and western blots of K562 cells treated with 7-d revealed an appreciable G2/M cycle arrest and apoptosis in a dose and time-dependent manner via p53-independent pathway. A striking increase in "Comet tail" formation and γ-H2AX expression showed that DNA double strand breaks (DSB) were caused by 7-d treatment. ATM/ATR signaling was reported to connect E2F1 induction with apoptosis in response to DNA damage. Indeed, 7-d-induced G2/M arrest and apoptosis were antagonized by ATM/ATR signaling inhibitor, Caffeine, which suggested that ATM/ATR signaling was activated by 7-d treatment. Furthermore, the increased expression of E2F1, p73, and Apaf-1 and p73 dissociation from HDM2 was induced by 7-d treatment, however, knockout of E2F1 expression reversed p73, Apaf-1, and p21(Cip1/WAF1) expression, reactivated cell cycle progression, and inhibited 7-d-induced apoptosis. Altogether our results for the first time indicate that 7-d mediates its growth inhibitory effects on CML p53-deficient cells via the activation of an E2F1-dependent mitochondrial and cell cycle checkpoint signaling pathway which subsequently targets p73, Apaf-1, and p21(Cip1/WAF1). SN - 1097-4644 UR - https://www.unboundmedicine.com/medline/citation/22593008/E2F1_dependent_pathways_are_involved_in_amonafide_analogue_7_d_induced_DNA_damage_G2/M_arrest_and_apoptosis_in_p53_deficient_K562_cells_ L2 - https://doi.org/10.1002/jcb.24194 DB - PRIME DP - Unbound Medicine ER -