Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl

AbstractChemoresistance is a major hurdle in anti-cancer therapy. Growing evidence indicates that integrin-mediated cell adhesion to extracellular matrix plays a major role in chemoresistance. However, the underlying mechanisms are not fully understood. We have previously shown that the collagen-binding integrin α2β1 promoted doxorubicin resistance in acute T cell lymphoblastic leukemia (T-ALL). In this study, we found that acute myeloid leukemia (AML) cell lines also express α2β1 integrin and collagen promoted their chemoresistance as well. Furthermore, we found that high levels of α2 integrin correlate with worse overall survival in AML. Our results showed that doxorubicin-induced apoptosis in leukemic cells is associated with activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) and that collagen inhibited this pathway. The protective effect of collagen is associated with the inhibition of Rac1-induced DNA damage as evaluated by the comet assay and the phosphorylated levels of histone H2AX (γ-H2AX). Together these results show that by inhibiting pro-apoptotic Rac1, α2β1 integrin can be a major pathway protecting leukemic cells from genotoxic agents and may thus represent an important therapeutic target in anti-cancer treatment.

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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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Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03369-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ding-fang Zhang ◽

Zhi-chun Yang ◽

Jian-qiang Chen ◽

Xiang-xiang Jin ◽

Yin-da Qiu ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Dna Damage ◽

Cell Adhesion ◽

Anticancer Activity ◽

Cancer Cells ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Dna Damage And Repair ◽

Castration Resistant

Abstract Background Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. Methods The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), β-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. Results The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. Conclusion Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

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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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Nuclear translocation of dihydrofolate reductase is not a pre-requisite for DNA damage induced apoptosis

APOPTOSIS ◽

10.1007/s10495-009-0343-9 ◽

2009 ◽

Vol 14 (5) ◽

pp. 699-710 ◽

Cited By ~ 5

Author(s):

Ting-Ting Yuan ◽

Ying Huang ◽

Ci-Xiang Zhou ◽

Yun Yu ◽

Li-Shun Wang ◽

...

Keyword(s):

Dna Damage ◽

Dihydrofolate Reductase ◽

Nuclear Translocation ◽

Induced Apoptosis

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Live Free or Die: Cell-Cell Adhesion Regulates Sensitivity to Trail-Induced Apoptosis

Developmental Cell ◽

10.1016/j.devcel.2014.06.031 ◽

2014 ◽

Vol 30 (1) ◽

pp. 3-4 ◽

Cited By ~ 2

Author(s):

Lisa L. Gallegos ◽

Joan S. Brugge

Keyword(s):

Cell Adhesion ◽

Induced Apoptosis ◽

Cell Cell

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Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase

Biochemical Journal ◽

10.1042/bj20061778 ◽

2007 ◽

Vol 405 (3) ◽

pp. 617-623 ◽

Cited By ~ 50

Author(s):

Emma V. Jones ◽

Mark J. Dickman ◽

Alan J. Whitmarsh

Keyword(s):

Dna Damage ◽

Stress Responses ◽

Tumour Progression ◽

Chemotherapeutic Agents ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

P53 Family ◽

Jnk Pathway ◽

Mitogen Activated Protein ◽

Induced Apoptosis

The JNK (c-Jun N-terminal kinase)/mitogen-activated protein kinase signalling pathway is a major mediator of stress responses in cells, including the response to DNA damage. DNA damage also causes the stabilization and activation of p73, a member of the p53 family of transcription factors. p73, like p53, can mediate apoptosis by up-regulating the expression of pro-apoptotic genes, including Bax (Bcl2-associated X protein) and PUMA (p53 up-regulated modulator of apoptosis). Changes in p73 expression have been linked to tumour progression, particularly in neuroblastomas, whereas in tumours that feature inactivated p53 there is evidence that p73 may mediate the apoptotic response to chemotherapeutic agents. In the present study, we demonstrate a novel link between the JNK signalling pathway and p73. We use pharmacological and genetic approaches to show that JNK is required for p73-mediated apoptosis induced by the DNA damaging agent cisplatin. JNK forms a complex with p73 and phosphorylates it at several serine and threonine residues. The mutation of JNK phosphorylation sites in p73 abrogates cisplatin-induced stabilization of p73 protein, leading to a reduction in p73 transcriptional activity and reduced p73-mediated apoptosis. Our results demonstrate that the JNK pathway is an important regulator of DNA damage-induced apoptosis mediated by p73.

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