FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage

Chung, Young-Min; Park, See‐Hyoung; Tsai, Wen Bin; Wang, Shih Ya; Ikeda, Masa Aki; Berek, Jonathan S.; Chen, David J.; Hu, Mickey C.T.

doi:10.1038/ncomms2008

Cited by 74 publications

(75 citation statements)

References 59 publications

(78 reference statements)

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“…Immunofluorescence experiments on HCC1937 and HCC1937 1 BRCA1 cells were conducted as described previously (Chung et al, 2012;Hu et al, 2014). Briefly, cells were grown on glass coverslips.…”

Section: Methodsmentioning

confidence: 99%

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The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro

Chen¹,

Zhou

Zhang

et al. 2015

Mol Pharmacol

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COH29 [N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide], a novel antimetabolite drug developed at City of Hope Cancer Center, has anticancer activity that stems primarily from the inhibition of human ribonucleotide reductase (RNR). This key enzyme in deoxyribonucleotide biosynthesis is the target of established clinical agents such as hydroxyurea and gemcitabine because of its critical role in DNA replication and repair. Herein we report that BRCA-1-defective human breast cancer cells are more sensitive than wild-type BRCA-1 counterparts to COH29 in vitro and in vivo. Microarray gene expression profiling showed that COH29 reduces the expression of DNA repair pathway genes, suggesting that COH29 interferes with these pathways. It is well established that BRCA1 plays a role in DNA damage repair, especially homologous recombination (HR) repair, to maintain genome integrity. In BRCA1-defective HCC1937 breast cancer cells, COH29 induced more double-strand breaks (DSBs) and DNA-damage response than in HCC1937 1 BRCA1 cells. By EJ5-and DR-green fluorescent protein (GFP) reporter assay, we found that COH29 could inhibit nonhomologous end joining (NHEJ) efficiency and that no HR activity was detected in HCC1937 cells, suggesting that repression of the NHEJ repair pathway may be involved in COH29-induced DSBs in BRCA1-deficient HCC1937 cells. Furthermore, we observed an accumulation of nuclear Rad51 foci in COH29-treated HCC1937 1 BRCA1 cells, suggesting that BRCA1 plays a crucial role in repairing and recovering druginduced DNA damage by recruiting Rad51 to damage sites. In summary, we describe here additional biologic effects of the RNR inhibitor COH29 that potentially strengthen its use as an anticancer agent.

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Section: Methodsmentioning

confidence: 99%

“…Protein concentrations of all fractions were determined using Bio-Rad Protein Assay (Bio-Rad Laboratories, Hercules, CA). Immunoblotting was performed as described previously (Chung et al, 2012;Hu et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro

Chen¹,

Zhou

Zhang

et al. 2015

Mol Pharmacol

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“…Thus, GP protects N2a cells at multiple steps. On the one hand, up-regulation of Akt leads to an increase of Bcl2 expression [34], which promotes cell survival [35] but on the other hand, down-regulation of FOXO3 [36] and p53 [37,38] results in the promotion of apoptosis. This shows that GP has multiple effects on cell death and survival.…”

Section: Discussionmentioning

confidence: 99%

The herbal compound geniposide rescues formaldehyde-induced apoptosis in N2a neuroblastoma cells

Chen

Sun

Wang

et al. 2014

Sci. China Life Sci.

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The herbal medicine Tong Luo Jiu Nao (TLJN) contains geniposide (GP) and ginsenoside Rg1 at a molar ratio of 10:1. Rg1 is the major component of another herbal medicine, panax notoginseng saponin (PNS). TLJN has been shown to strengthen brain function in humans, and in animals it improves learning and memory. We have previously shown that TLJN reduces amyloidogenic processing in Alzheimer's disease (AD) mouse models. Together this suggests TLJN may be a potential treatment for patients with dementia. Because chronic damage of the central nervous system by formaldehyde (FA) has been presented as a risk factor for age-associated cognitive dysfunction, in the present study we investigated the protective effect of both TLJN and GP in neuron-like cells exposed to FA. FA-exposed murine N2a neuroblastoma cells were incubated with TLJN, its main ingredient GP, as well as PNS, to measure cell viability and morphology, the rate of apoptosis and expression of genes encoding Akt, FOXO3, Bcl2 and p53. The CCK-8 assay, cytoskeletal staining and flow cytometry were used to test cell viability, morphology and apoptosis, respectively. Fluorescent quantitative real-time PCR (qRT-PCR) was used to monitor changes in gene expression, and HPLC to determine the rate of FA clearance. Treatment of N2a cells with 0.09 mmol L 1 FA for 24 h significantly reduced cell viability, changed cell morphology and promoted apoptosis. Both TLJN and GP conferred neuroprotection to FA-treated N2a cells, whereas PNS, which had to be used at lower concentrations because of its toxicity, did not. Our data demonstrate that TLJN can rescue neuronal damage caused by FA and that its main ingredient, GP, has a major role in this efficacy. This presents purified GP as a drug or lead compound for the treatment of AD. FA is a colorless, irritating gas with a high oxidation capa-

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“…145 However, the relationship between AKT and DNA damage signaling is complex, and many other targets that are inhibited by AKT actually enhance DNA damage checkpoints and repair. For example, FOXO3A has been shown to directly associate with ATM, p53, and Chk2, enhancing the activation of these proteins, 146,147 and to regulate both the G1 148 and G2/M 149 DNA damage checkpoints. Thus, FOXO3A inactivation through AKT phosphorylation might be expected to impair the DDR.…”

Section: Combination Of Pi3k and Mek Inhibitorsmentioning

confidence: 99%