4-Hydroxynonenal Induces G2/M Phase Cell Cycle Arrest by Activation of the Ataxia Telangiectasia Mutated and Rad3-related Protein (ATR)/Checkpoint Kinase 1 (Chk1) Signaling Pathway

Chaudhary, Pankaj; Sharma, Rajendra; Sahu, Mukesh; Vishwanatha, Jamboor K.; Awasthi, Sanjay; Awasthi, Yogesh C.

doi:10.1074/jbc.m113.467662

Cited by 49 publications

(60 citation statements)

References 70 publications

(89 reference statements)

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“…Downregulation of cyclin B1‐CDK1 expression was more evident than that of cyclin A‐CDK2 or cyclin A‐CDK1 in MB cells following treatment with IAP antagonist or in combination with vincristine or cisplatin. These data are in accordance with other studies showing that attenuation of the cyclin B1‐CDK1 complex, which is critical for entry into mitotic phase, can be seen in cancer cells arresting in the G2/M transition 30, 31…”

Section: Resultssupporting

confidence: 93%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small‐molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase‐3/7‐activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1‐CDK1 and cyclin A‐CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent‐G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1‐mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.

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Section: Resultssupporting

confidence: 93%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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“…The DDR preserves genetic stability by detecting DNA lesions, activating cell cycle checkpoints and promoting DNA damage repair [18][19][20][21]. The common denominator integrating these forms of genotoxic stresses and eliciting the signalling cascade is increased production of ROS as harbinger to DNA damage [22][23][24][25][26][27]. Chemical agents such as drugs used in cancer chemotherapy are also able to induce some form of DNA lesions [28].…”

Section: Introductionmentioning

confidence: 99%

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Khalil¹,

Deeni²

2015

Biodiscovery

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of the antioxidant response (AR) pathway and functions as a transcription factor for basal and oxidative stress-induced expression of a battery of detoxification enzymes and cytoprotective genes. Recent evidence has also demonstrated a role of NRF2 in driving resistance of numerous cancers to chemotherapeutic agents. ATM and ATR are serine/threonine kinases that are activated following DNA damage and function as central components of DNA Damage Response (DDR) pathway. Activities of these kinases cause cell cycle arrest and activate DNA repair signals leading to cytoprotection against genotoxic agents. In this study, we elucidated the roles of ATM-and ATR-dependent DDR and NRF2-mediated AR pathways in promoting cytoprotection following cisplatin challenge in ovarian cancer cell line models. We also determined whether these pathways were inter-dependent for full activation following genotoxic insults and as such demonstrated crosstalk in their signaling mechanism to elicit cytoprotective pathways. Treatment with cisplatin caused NRF2 induction and generation of reactive oxygen species (ROS) that caused cytotoxicity in ovarian cancer cells. This was attenuated by the ROS scavenger N-Acetyl cysteine, implicating NRF2 function in cytoprotection against cisplatin. Treatment with retinoic acid (RA) caused down regulation of NRF2, disruption of AR pathway, significant accumulation of ROS and enhanced cisplatin cytotoxicity. Interestingly, RA treatment also led to repression of total ATM and ATR proteins and aberrant DDR activation following cisplatin challenge. In order to determine whether the RA induced ATM and ATR repression was dependent on NRF2 inhibition, we silenced NRF2 using SiRNA. This caused transcriptional repression of both ATM and ATR expression as determined by their promoter driven luciferase assays. Thus, NRF2 inhibition led to DDR suppression by down-regulating ATM and ATR that led to enhanced cytotoxicity. These findings demonstrate mechanism of crosstalk between the AR and the DDR pathways and extend the scope of NRF2 in promoting cancer therapeutic resistance.

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“…Since we did not observe the reduction of phospho-ERK in NT2/D1 cells after nanomolar levels of TBT exposure (data not shown), the mechanism of inducing G2 arrest may differ depending on the TBT levels and cell type. Moreover, several chemical stressors have been reported to cause G2/M cell cycle arrest through the protein reduction of cell cycle regulators (Chaudhary et al, 2013;Nam et al, 2010;Ouyang et al, 2009). For instance, 4-Hydroxynonenal, an inducer of oxidative stress, causes DNA damage and induces G2/M cell cycle arrest in hepatocellular carcinoma HepG2 and Hep3B cells, following reduction of cdc25C and thereafter cyclin B1 proteins in a p53-independent manner (Chaudhary et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Protein levels of these cell cycle regulators are strictly regulated during cell cycle progression. Ultraviolet irradiation or toxic drugs are known to cause G2 arrest by the inactivation of cyclin B1/Cdk1 via p53 induction followed by the upregulation of p21, a Cdk inhibitor and/or cdc25C downregulation by degradation (Chaudhary et al, 2013;Kawabe, 2004;Nam et al, 2010;Ouyang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Tributyltin induces G2/M cell cycle arrest via NAD<sup>+</sup>-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

et al. 2016

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-Organotin compounds, such as tributyltin (TBT), are well-known endocrine-disrupting chemicals (EDCs). We have recently reported that TBT induces growth arrest in the human embryonic carcinoma cell line NT2/D1 at nanomolar levels by inhibiting NAD + -dependent isocitrate dehydrogenase (NAD-IDH), which catalyzes the irreversible conversion of isocitrate to α-ketoglutarate. However, the molecular mechanisms by which NAD-IDH mediates TBT toxicity remain unclear. In the present study, we examined whether TBT at nanomolar levels affects cell cycle progression in NT2/D1 cells. Propidium iodide staining revealed that TBT reduced the ratio of cells in the G1 phase and increased the ratio of cells in the G2/M phase. TBT also reduced cell division cycle 25C (cdc25C) and cyclin B1, which are key regulators of G2/M progression. Furthermore, apigenin, an inhibitor of NAD-IDH, mimicked the effects of TBT. The G2/M arrest induced by TBT was abolished by NAD-IDHα knockdown. Treatment with a cellpermeable α-ketoglutarate analogue recovered the effect of TBT, suggesting the involvement of NAD-IDH. Taken together, our data suggest that TBT at nanomolar levels induced G2/M cell cycle arrest via NAD-IDH in NT2/D1 cells. Thus, cell cycle analysis in embryonic cells could be used to assess cytotoxicity associated with nanomolar level exposure of EDCs.

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4-Hydroxynonenal Induces G2/M Phase Cell Cycle Arrest by Activation of the Ataxia Telangiectasia Mutated and Rad3-related Protein (ATR)/Checkpoint Kinase 1 (Chk1) Signaling Pathway

Cited by 49 publications

References 70 publications

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Tributyltin induces G2/M cell cycle arrest via NAD<sup>+</sup>-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

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