DNA-damage induced cell death in yap1;wwtr1 mutant epidermal basal cells

In a previous study, it was reported that Yap1 and Wwtr1 in zebrafish regulates the morphogenesis of the posterior body and epidermal fin fold (Kimelman, D., et al. 2017). We report here that DNA damage induces apoptosis of epidermal basal cells (EBCs) in zebrafish yap1-/-;wwtr1-/- embryos. Specifically, these mutant EBCs exhibit active Caspase-3, Caspase-8 and γH2AX, consistent with DNA damage serving as a stimulus of the extrinsic apoptotic pathway in epidermal cells. Live imaging of zebrafish epidermal cells reveals a steady growth of basal cell size in the developing embryo, but this growth is inhibited in mutant basal cells followed by apoptosis, leading to the hypothesis that factors underscoring cell size play a role in this DNA damage-induced apoptosis phenotype. We tested two of these factors using cell stretching and substrate stiffness assays, and found that HaCaT cells cultured on stiff substrates exhibit more numerous γH2AX foci compared to ones cultured on soft substrates. Thus, we propose that substrate rigidity modulates genomic stress in the developing epidermal cell, and that Yap1 and Wwtr1 are required for its survival.

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Protective Effects of Nargenicin A1 against Tacrolimus-Induced Oxidative Stress in Hirame Natural Embryo Cells

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16061044 ◽

2019 ◽

Vol 16 (6) ◽

pp. 1044 ◽

Cited By ~ 2

Author(s):

Cheol Park ◽

Da Kwon ◽

Su Hwang ◽

Min Han ◽

Jin-Woo Jeong ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Caspase 3 ◽

B Cell Lymphoma ◽

Ros Generation ◽

Protective Effects ◽

Apoptotic Pathway ◽

Embryo Cells ◽

Ros Scavenger ◽

Induced Apoptosis

Tacrolimus is widely used as an immunosuppressant to reduce the risk of rejection after organ transplantation, but its cytotoxicity is problematic. Nargenicin A1 is an antibiotic extracted from Nocardia argentinensis and is known to have antioxidant activity, though its mode of action is unknown. The present study was undertaken to evaluate the protective effects of nargenicin A1 on DNA damage and apoptosis induced by tacrolimus in hirame natural embryo (HINAE) cells. We found that reduced HINAE cell survival by tacrolimus was due to the induction of DNA damage and apoptosis, both of which were prevented by co-treating nargenicin A1 or N-acetyl-l-cysteine, a reactive oxygen species (ROS) scavenger, with tacrolimus. In addition, apoptosis induction by tacrolimus was accompanied by increases in ROS generation and decreases in adenosine triphosphate (ATP) levels caused by mitochondrial dysfunction, and these changes were significantly attenuated in the presence of nargenicin A1, which further indicated tacrolimus-induced apoptosis involved an oxidative stress-associated mechanism. Furthermore, nargenicin A1 suppressed tacrolimus-induced B-cell lymphoma-2 (Bcl-2) down-regulation, Bax up-regulation, and caspase-3 activation. Collectively, these results demonstrate that nargenicin A1 protects HINAE cells against tacrolimus-induced DNA damage and apoptosis, at least in part, by scavenging ROS and thus suppressing the mitochondrial-dependent apoptotic pathway.

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Human Embryonic Stem Cells Acquire Responsiveness to TRAIL upon Exposure to Cisplatin

Stem Cells International ◽

10.1155/2019/4279481 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Lucie Pešková ◽

Vladimír Vinarský ◽

Tomáš Bárta ◽

Aleš Hampl

Keyword(s):

Stem Cells ◽

Dna Damage ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Caspase 3 ◽

Embryonic Stem ◽

Caspase 8 ◽

Apoptotic Pathway ◽

Extrinsic Apoptotic Pathway ◽

Induced Apoptosis

Tumor necrosis factor-related apoptosis-inducing ligand—TRAIL—is a protein operating as a ligand capable of inducing apoptosis particularly in cancerously transformed cells, while normal healthy cells are typically nonresponsive. We have previously demonstrated that pluripotent human embryonic stem cells (hESC) are also refractory to TRAIL, even though they express all canonical components of the death receptor-induced apoptosis pathway. In this study, we have examined a capacity of DNA damage to provoke sensitivity of hESC to TRAIL. The extent of DNA damage, behavior of molecules involved in apoptosis, and response of hESC to TRAIL were investigated. The exposure of hESC to 1 μM and 2 μM concentrations of cisplatin have led to the formation of 53BP1 and γH2AX foci, indicating the presence of double-strand breaks in DNA, without affecting the expression of proteins contributing to mitochondrial membrane integrity. Interestingly, cisplatin upregulated critical components of the extrinsic apoptotic pathway—initiator caspase 8, effector caspase 3, and the cell death receptors. The observed increase of expression of the extrinsic apoptotic pathway components was sufficient to sensitize hESC to TRAIL-induced apoptosis; immense cell dying accompanied by enhanced PARP cleavage, processing of caspase 8, and full activation of caspase 3 were all observed after the treatment combining cisplatin and TRAIL. Finally, we have demonstrated the central role of caspase 8 in this process, since its downregulation abrogated the sensitizing effect of cisplatin.

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Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment

International Journal of Surgical Oncology ◽

10.1155/2012/862879 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Satoshi Tanida ◽

Tsutomu Mizoshita ◽

Keiji Ozeki ◽

Hironobu Tsukamoto ◽

Takeshi Kamiya ◽

...

Keyword(s):

Gastric Cancer ◽

Dna Damage ◽

Molecular Mechanisms ◽

Cisplatin Resistance ◽

Drug Uptake ◽

Apoptotic Pathway ◽

Damage Recognition ◽

Cisplatin Sensitivity ◽

Induced Apoptosis ◽

Dna Damage Recognition

Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis. Cisplatin resistance arises through a multifactorial mechanism involving reduced drug uptake, increased drug inactivation, increased DNA damage repair, and inhibition of transmission of DNA damage recognition signals to the apoptotic pathway. In addition, a new mechanism has recently been revealed, in which the oncoprotein c-Myc suppresses bridging integrator 1 (BIN1), thereby releasing poly(ADP-ribose)polymerase 1, which results in increased DNA repair activity and allows cancer cells to acquire cisplatin resistance. The present paper focuses on the molecular mechanisms of cisplatin-induced apoptosis and of cisplatin resistance, in particular on the involvement of BIN1 in the maintenance of cisplatin sensitivity.

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Interferon gamma/STAT1 signalling prevents hepatocarcinogenesis by sensitizing for p53-induced apoptosis in response to DNA-damage

Zeitschrift für Gastroenterologie ◽

10.1055/s-2008-1037515 ◽

2008 ◽

Vol 46 (01) ◽

Author(s):

J Schrader ◽

S Zander ◽

S Lüth ◽

A Lohse ◽

J Herkel

Keyword(s):

Dna Damage ◽

Interferon Gamma ◽

Induced Apoptosis

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Thymoquinone sensitizes human hepatocarcinoma cells to TRAIL-induced apoptosis via oxidative DNA damage

DNA Repair ◽

10.1016/j.dnarep.2021.103117 ◽

2021 ◽

pp. 103117

Author(s):

Ruikui Zhang ◽

Tao Wu ◽

Peipei Zheng ◽

Ming Liu ◽

Guixiang Xu ◽

...

Keyword(s):

Dna Damage ◽

Oxidative Dna Damage ◽

Hepatocarcinoma Cells ◽

Induced Apoptosis ◽

Human Hepatocarcinoma Cells

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Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis

Cell Death and Disease ◽

10.1038/s41419-020-03381-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Takuma Nakatsuka ◽

Keisuke Tateishi ◽

Hiroyuki Kato ◽

Hiroaki Fujiwara ◽

Keisuke Yamamoto ◽

...

Keyword(s):

Dna Damage ◽

Epigenetic Modification ◽

Histone Methyltransferase ◽

Preventive Strategy ◽

Tumor Initiation ◽

Liver Transcriptome ◽

Genetic Abnormalities ◽

Responsive Element ◽

Induced Apoptosis

AbstractWhile the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9aΔHep) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in the G9aΔHep and wild-type livers, more apoptotic hepatocytes were detected in the G9aΔHep liver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in the G9aΔHep liver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of the Bcl-G gene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.

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Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine, DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis

Molecules ◽

10.3390/molecules26154417 ◽

2021 ◽

Vol 26 (15) ◽

pp. 4417

Author(s):

Rabin Neupane ◽

Saloni Malla ◽

Mariam Sami Abou-Dahech ◽

Swapnaa Balaji ◽

Shikha Kumari ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Colon Cancer Cells ◽

Apoptotic Pathway ◽

Anticancer Efficacy ◽

Colon Cell ◽

Ic50 Values ◽

Induced Apoptosis

A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.

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ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. VOLUME 283 (2008) PAGES 6572-6583

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)71575-9 ◽

2008 ◽

Vol 283 (22) ◽

pp. 15512

Author(s):

Navjotsingh Pabla ◽

Shuang Huang ◽

Qing-Sheng Mi ◽

Rene Daniel ◽

Zheng Dong

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Damage Response ◽

P53 Activation ◽

Induced Apoptosis

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Urea sensitizes mIMCD3 cells to heat shock-induced apoptosis: protection by NaCl

AJP Cell Physiology ◽

10.1152/ajpcell.2001.280.3.c614 ◽

2001 ◽

Vol 280 (3) ◽

pp. C614-C620 ◽

Cited By ~ 11

Author(s):

Chantal Colmont ◽

Stéphanie Michelet ◽

Dominique Guivarc'h ◽

Germain Rousselet

Keyword(s):

Heat Shock ◽

Heat Shock Response ◽

Heat Sensitivity ◽

Osmotic Gradient ◽

Water Reabsorption ◽

Apoptotic Pathway ◽

Shock Response ◽

Induced Apoptosis ◽

Shock Proteins ◽

Dose Dependent

Urea, with NaCl, constitutes the osmotic gradient that allows water reabsorption in mammalian kidneys. Because NaCl induces heat shock proteins, we tested the responses to heat shock of mIMCD3 cells adapted to permissive urea and/or NaCl concentrations. We found that heat-induced cell death was stronger after adaptation to 250 mM urea. This effect was reversible, dose dependent, and, interestingly, blunted by 125 mM NaCl. Moreover, we have shown that urea-adapted cells engaged in an apoptotic pathway upon heat shock, as shown by DNA laddering. This sensitization is not linked to a defect in the heat shock response, because the induction of HSP70 was similar in isotonic and urea-adapted cells. Moreover, it is not linked to the presence of urea inside cells, because washing urea away did not restore heat resistance and because applying urea and heat shock at the same time did not lead to heat sensitivity. Together, these results suggest that urea modifies the heat shock response, leading to facilitated apoptosis.

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