The Extract of Leonurus sibiricus Transgenic Roots with AtPAP1 Transcriptional Factor Induces Apoptosis via DNA Damage and Down Regulation of Selected Epigenetic Factors in Human Cancer Cells

The transmembrane adaptor protein Cbp (or PAG1) functions as a suppressor of Src-mediated tumor progression by promoting the inactivation of Src. The expression of Cbp is down-regulated in Src-transformed cells and in various human cancer cells, suggesting a potential role for Cbp as a tumor suppressor. However, the mechanisms underlying the down-regulation of Cbp remain unknown. The present study shows that Cbp expression is down-regulated by epigenetic histone modifications via the MAPK/PI3K pathway. In mouse embryonic fibroblasts, transformation by oncogenic Src and Ras induced a marked down-regulation of Cbp expression. The levels of Cbp expression were inversely correlated with the activity of MEK and Akt, and Cbp down-regulation was suppressed by inhibiting MEK and PI3K. Src transformation did not affect the stability of Cbp mRNA, the transcriptional activity of the cbp promoter, or the DNA methylation status of the cbp promoter CpG islands. However, Cbp expression was restored by treatment with histone deacetylase (HDAC) inhibitors and by siRNA-mediated knockdown of HDAC1/2. Src transformation significantly decreased the acetylation levels of histone H4 and increased the trimethylation levels of histone H3 lysine 27 in the cbp promoter. EGF-induced Cbp down-regulation was also suppressed by inhibiting MEK and HDAC. Furthermore, the inhibition of MEK or HDAC restored Cbp expression in human cancer cells harboring Cbp down-regulation through promoter hypomethylation. These findings suggest that Cbp down-regulation is primarily mediated by epigenetic histone modifications via oncogenic MAPK/PI3K pathways in a subset of cancer cells.

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p53-Independent Down-Regulation of Mdm2 in Human Cancer Cells Treated with Adriamycin

Molecular Cell Biology Research Communications ◽

10.1006/mcbr.2000.0201 ◽

2000 ◽

Vol 3 (2) ◽

pp. 122-128 ◽

Cited By ~ 10

Author(s):

Yongxian Ma ◽

Renqi Yuan ◽

Qinghui Meng ◽

Itzhak D. Goldberg ◽

Eliot M. Rosen ◽

...

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Down Regulation ◽

Human Cancer Cells

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Differential response between the p53 ubiquitin–protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells

Experimental Cell Research ◽

10.1016/j.yexcr.2006.07.005 ◽

2006 ◽

Vol 312 (17) ◽

pp. 3370-3378 ◽

Cited By ~ 22

Author(s):

Wenrui Duan ◽

Li Gao ◽

Xin Wu ◽

Yang Zhang ◽

Gregory A. Otterson ◽

...

Keyword(s):

Dna Damage ◽

Cancer Cells ◽

Human Cancer ◽

Differential Response ◽

Human Cancer Cells ◽

Protein Ligases

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Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells

Frontiers in Oncology ◽

10.3389/fonc.2021.667920 ◽

2021 ◽

Vol 11 ◽

Author(s):

Mengfei Yao ◽

Yaqian Wu ◽

Yanan Cao ◽

Haijing Liu ◽

Ningning Ma ◽

...

Keyword(s):

Dna Damage ◽

Cancer Cells ◽

Genomic Dna ◽

Human Cancer ◽

Cancer Cell Line ◽

Growth And Survival ◽

Human Cancer Cells ◽

Cytoplasmic Dna ◽

Chemical Inhibitors ◽

Nuclear Damage

The cGAS (GMP-AMP synthase)-mediated senescence-associated secretory phenotype (SASP) and DNA-induced autophagy (DNA autophagy) have been extensively investigated in recent years. However, cGAS-mediated autophagy has not been elucidated in cancer cells. The described investigation revealed that active DNA autophagy but not SASP activity could be detected in the BT-549 breast cancer cell line with high micronucleus (MN) formation. DNA autophagy was identified as selective autophagy of free genomic DNA in the cytoplasm but not nucleophagy. The process of DNA autophagy in the cytosol could be initiate by cGAS and usually cooperates with SQSTM1-mediated autophagy of ubiquitinated histones. Cytoplasmic DNA, together with nuclear proteins such as histones, could be derived from DNA replication-induced nuclear damage and MN collapse. The inhibition of autophagy through chemical inhibitors as well as the genomic silencing of cGAS or SQSTM1 could suppress the growth and survival of cancer cells, and induced DNA damage could increase the sensitivity to these inhibitors. Furthermore, expanded observations of several other kinds of human cancer cells indicated that high relative DNA autophagy or enhancement of DNA damage could also increase or sensitize these cells to inhibition of DNA autophagy.

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The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells

Cells ◽

10.3390/cells9051161 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1161 ◽

Cited By ~ 2

Author(s):

Magdalena Cal ◽

Irwin Matyjaszczyk ◽

Ireneusz Litwin ◽

Daria Augustyniak ◽

Rafał Ogórek ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Dna Damage ◽

Cancer Cells ◽

Human Cancer ◽

Reactive Oxygen ◽

Atp Depletion ◽

Mitochondrial Enzymes ◽

Oxygen Species ◽

Human Cancer Cells ◽

The Impact

3-bromopyruvate (3-BP) is a small molecule with anticancer and antimicrobial activities. 3-BP is taken up selectively by cancer cells’ mono-carboxylate transporters (MCTs), which are highly overexpressed by many cancers. When 3-BP enters cancer cells it inactivates several glycolytic and mitochondrial enzymes, leading to ATP depletion and the generation of reactive oxygen species. While mechanisms of 3-BP uptake and its influence on cell metabolism are well understood, the impact of 3-BP at certain concentrations on DNA integrity has never been investigated in detail. Here we have collected several lines of evidence suggesting that 3-BP induces DNA damage probably as a result of ROS generation, in both yeast and human cancer cells, when its concentration is sufficiently low and most cells are still viable. We also demonstrate that in yeast 3-BP treatment leads to generation of DNA double-strand breaks only in S-phase of the cell cycle, possibly as a result of oxidative DNA damage. This leads to DNA damage, checkpoint activation and focal accumulation of the DNA response proteins. Interestingly, in human cancer cells exposure to 3-BP also induces DNA breaks that trigger H2A.X phosphorylation. Our current data shed new light on the mechanisms by which a sufficiently low concentration of 3-BP can induce cytotoxicity at the DNA level, a finding that might be important for the future design of anticancer therapies.

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