PNAS-4, an Early DNA Damage Response Gene, Induces S Phase Arrest and Apoptosis by Activating Checkpoint Kinases in Lung Cancer Cells

Zhu, Yong‐Guan; Guo, Wenhao; Yang, Jun; Li, Lei; Wang, Meiliang; Lei, Yi; Wan, Yang; Zhao, Xinyu; Luo, Na; Cheng, Ping; Liu, Xinyu; Nie, Chao; Peng, Yong; Tong, Aiping; Wei, Yuquan

doi:10.1074/jbc.m115.658419

Cited by 31 publications

(28 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3). This phenomenon has been reported previously and has an important implications for the approach, particularly in the development of combinatorial drug treatments that target the MAPK signaling pathway (44–46). Our results demonstrate that ML264 significantly inhibits cellular proliferation, and mitosis in particular, in both in vitro and in vivo systems, as shown by analyses of a) mitotic figures in DLD-1 cells treated in culture (Figs.…”

Section: Resultssupporting

confidence: 70%

ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer

Sabando

Wang

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Colorectal cancer (CRC) is one of the leading causes of cancer mortality in Western civilization. Studies have shown that CRC arises as a consequence of the modification of genes that regulate important cellular functions. Deregulation of the WNT and RAS/MAPK/PI3K signaling pathways has been shown to be important in the early stages of CRC development and progression. Krüppel-like factor 5 (KLF5) is a transcription factor that is highly expressed in the proliferating intestinal crypt epithelial cells. Previously, we showed that KLF5 is a mediator of RAS/MAPK and WNT signaling pathways under homeostatic conditions and that it promotes their tumorigenic functions during the development and progression of intestinal adenomas. Recently, using an ultrahigh-throughput screening (uHTS) approach we identified a number of novel small molecules that have the potential to provide therapeutic benefits for colorectal cancer by targeting KLF5 expression. In the current study, we show that an improved analog of one of these screening hits, ML264, potently inhibits proliferation of CRC cells in vitro through modifications of the cell cycle profile. Moreover, in an established xenograft mouse model of colon cancer, we demonstrate that ML264 efficiently inhibits growth of the tumor within five days of treatment. We show that this effect is caused by a significant reduction in proliferation and that ML264 potently inhibits the expression of KLF5 and EGR1, a transcriptional activator of KLF5. These findings demonstrate that ML264, or an analog may hold a promise as a novel therapeutic agent to curb the development and progression of colorectal cancer.

show abstract

Section: Resultssupporting

confidence: 70%

ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer

Sabando

Wang

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Chk1 and Chk2 are involved in channeling DNA damage signals from ATR and ATM in mammalian cells, respectively. Other research has shown that Chk2 at Thr68 is phosphorylated by ATM in response to DNA damage (43,44). Indeed, in the present study, 3-HT treatment led to the upregulation of p-ATM in A2780/CP70 cells.…”

Section: Discussionmentioning

confidence: 93%

3-Hydroxyterphenyllin, a natural fungal metabolite, induces apoptosis and S phase arrest in human ovarian carcinoma cells

Wang¹,

Compton²,

Rankin³

et al. 2017

International Journal of Oncology

View full text Add to dashboard Cite

In the present study, we evaluated 3-Hydroxyter-phenyllin (3-HT) as a potential anticancer agent using the human ovarian cancer cells A2780/CP70 and OVCAR-3, and normal human epithelial ovarian cells IOSE-364 as an in vitro model. 3-HT suppressed proliferation and caused cytotoxicity against A2780/CP70 and OVCAR-3 cells, while it exhibited lower cytotoxicity in IOSE-364 cells. Subsequently, we found that 3-HT induced S phase arrest and apoptosis in a dose-independent manner. Further investigation revealed that S phase arrest was related with DNA damage which mediated the ATM/p53/Chk2 pathway. Downregulation of cyclin D1, cyclin A2, cyclin E1, CDK2, CDK4 and Cdc25C, and the upregulation of Cdc25A and cyclin B1 led to the accumulation of cells in S phase. The apoptotic effect was confirmed by Hoechst 33342 staining, depolarization of mitochondrial membrane potential and activation of cleaved caspase-3 and PARP1. Additional results revealed both intrinsic and extrinsic apoptotic pathways were involved. The intrinsic apoptotic pathway was activated through decreasing the protein levels of Bcl2, Bcl-xL and procaspase-9 and increasing the protein level of Puma. The induction of DR5 and DR4 indicated that the extrinsic apoptotic pathway was also activated. Induction of ROS and activation of ERK were observed in ovarian cancer cells. We therefore concluded that 3-HT possessed anti-proliferative effect on A2780/CP70 and OVCAR-3 cells, induced S phase arrest and caused apoptosis. Taken together, we propose that 3-HT shows promise as a therapeutic candidate for treating ovarian cancer.

show abstract

“…It appears rather trivial that cell cycle arrest or dysfunction is associated with apoptosis [ 34 , 35 ]. E2F4 knockout mice exhibit an increased rate of cardiomyocyte apoptosis and this is mediated by several mechanisms.…”

Section: Discussionmentioning

confidence: 99%

The Histone Demethylase PHF8 Is Essential for Endothelial Cell Migration

Hitzel

Moll

et al. 2016

PLoS ONE

View full text Add to dashboard Cite

Epigenetic marks critically control gene expression and thus the cellular activity state. The functions of many epigenetic modifiers in the vascular system have not yet been studied. We screened for histone modifiers in endothelial cells and observed a fairly high expression of the histone plant homeodomain finger protein 8 (PHF8). Given its high expression, we hypothesize that this histone demethylase is important for endothelial cell function. Overexpression of PHF8 catalyzed the removal of methyl-groups from histone 3 lysine 9 (H3K9) and H4K20, whereas knockdown of the enzyme increased H3K9 methylation. Knockdown of PHF8 by RNAi also attenuated endothelial proliferation and survival. As a functional readout endothelial migration and tube formation was studied. PHF8 siRNA attenuated the capacity for migration and developing of capillary-like structures. Given the impact of PHF8 on cell cycle genes, endothelial E2F transcription factors were screened, which led to the identification of the gene repressor E2F4 to be controlled by PHF8. Importantly, PHF8 maintains E2F4 but not E2F1 expression in endothelial cells. Consistently, chromatin immunoprecipitation revealed that PHF8 reduces the H3K9me2 level at the E2F4 transcriptional start site, demonstrating a direct function of PHF8 in endothelial E2F4 gene regulation. Conclusion: PHF8 by controlling E2F4 expression maintains endothelial function.

show abstract

PNAS-4, an Early DNA Damage Response Gene, Induces S Phase Arrest and Apoptosis by Activating Checkpoint Kinases in Lung Cancer Cells

Cited by 31 publications

References 62 publications

ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer

ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer

3-Hydroxyterphenyllin, a natural fungal metabolite, induces apoptosis and S phase arrest in human ovarian carcinoma cells

The Histone Demethylase PHF8 Is Essential for Endothelial Cell Migration

Contact Info

Product

Resources

About