Activating transcription factor 3 interferes with p21 activation in histone deacetylase inhibitor-induced growth inhibition of epidermoid carcinoma cells

Hao, Zhenfeng; Su, Yirong; Wang, Congmin

doi:10.1007/s13277-014-2618-1

Cited by 5 publications

(4 citation statements)

References 31 publications

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“…G 2 -M arrest and the resistance of noncancerous cells to HDACi have been described previously (45) and reflect the presence of a G 2 checkpoint in normal cells, which is absent in the majority of cancer cells; abolishing the G 2 checkpoint using checkpoint kinase 1 abrogates this resistance (46). Our findings in bladder cancer that the reactivation of p21 is in parallel to the reactivation of ATF3 are in contrast to the observation made in epidermoid carcinoma, where ATF3 acts as an oncogenic activator (47).…”

Section: Discussionsupporting

confidence: 76%

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Sooraj

Cain

et al. 2016

Molecular Cancer Therapeutics

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Improved treatment strategies are required for bladder cancer due to frequent recurrence of low-grade tumors and poor survival rate from high-grade tumors with current therapies. Histone deacetylase inhibitors (HDACi), approved as single agents for specific lymphomas, have shown promising preclinical results in solid tumors but could benefit from identification of biomarkers for response. Loss of activating transcription factor 3 (ATF3) expression is a feature of bladder tumor progression and correlates with poor survival. We investigated the utility of measuring ATF3 expression as a marker of response to the HDACi pracinostat in bladder cancer models. Pracinostat treatment of bladder cancer cell lines reactivated the expression of ATF3, correlating with significant alteration in proliferative, migratory, and anchoragedependent growth capacities. Pracinostat also induced growth arrest at the G 0 -G 1 cell-cycle phase, coincident with the activation of tumor suppressor genes. In mouse xenograft bladder cancer models, pracinostat treatment significantly reduced tumor volumes compared with controls, accompanied by reexpression of ATF3 in nonproliferating cells from early to late stage of therapy and in parallel induced antiangiogenesis and apoptosis. Importantly, cells in which ATF3 expression was depleted were less sensitive to pracinostat treatment in vitro, exhibiting significantly higher proliferative and migratory properties. In vivo, control xenograft tumors were significantly more responsive to treatment than ATF3 knockdown xenografts. Thus, reactivation of ATF3 is an important factor in determining sensitivity to pracinostat treatment, both in vitro and in vivo, and could serve as a potential biomarker of response and provide a rationale for therapeutic utility in HDACi-mediated treatments for bladder cancer.

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Section: Discussionsupporting

confidence: 76%

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Sooraj

Cain

et al. 2016

Molecular Cancer Therapeutics

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“…In general, the p21 gene is regulated in a p53-dependent or/and p53-independent manner [3–8]. A recent study showed that TSA induces p21 expression via the down-regulation of ATF3 in A431 epidermoid carcinoma cells [30]. In HeLa cells, we observed similar effects of TSA on p21 and ATF3, whereas the other tested HDACIs induced both p21 and ATF3 expressions.…”

Section: Discussionsupporting

confidence: 59%

Regulatory mechanisms of fluvastatin and lovastatin for the p21 induction in human cervical cancer HeLa cells

et al. 2019

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p21, an inhibitor of cyclin-dependent kinase, functions as an oncogene or tumor suppressor depending on the context of a variety of extracellular and intracellular signals. The expression of p21 could be regulated at the transcriptional and/or post-translational levels. The p21 gene is well-known to be regulated in both p53-dependent and -independent manners. However, the detailed regulatory mechanisms of p21 messenger RNA and protein expression via statins remain unknown, and the possible application of statins as anticancer reagents remains to be controversial. Our data showed that the statins—fluvastatin and lovastatin—induced p21 expression as general histone deacetylase inhibitors in a p53-independent manner, which is mediated through various pathways, such as apoptosis, autophagy, cell cycle progression, and DNA damage, to be involved in the function of p21 in HeLa cells. The curative effect repositioning of digoxin, a cardiovascular medication, was combined with fluvastatin and lovastatin, and the results further implied that p21 induction is involved in a p53-dependent and p53-independent manner. Digoxin modified the effects of statins on ATF3, p21, p53, and cyclin D1 expression, while fluvastatin boosted its DNA damage effect and lovastatin impeded its DNA damage effect. Fluvastatin and lovastatin combined with digoxin further support the localization specificity of their interactivity with our subcellular localization data. This study will not only clarify the regulatory mechanisms of p21 induction by statins but will also shed light on the repurposing of widely cardiovascular medications for the treatment of cervical cancer.

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“…These findings can be attributed to BM-MSCs' potential to ameliorate apoptosis inducers, either hyperglycemia or oxidative stress or beta-cell inflammatory environment or ER stress according to the result of the present work that reduced further renal tissue damage and apoptosis (Bugliani et al, 2019). In addition, these findings could be reverted to the elevated expression of activated transcription factor 3 (ATF3) that inhibits apoptosis via downregulating the expression of proapoptotic factor P21 (Hao et al, 2014) on the other hand. Altogether, BM-MSCs could ameliorate beta cell apoptosis in a molecular pathway (ATF3+/P21-/FAS-/FAS L -/BAX -/caspase-3-/ P53-/BCL2+) or (insulin+/hyperglycemia-/redox-/ER stress-/inflammatory cytokines-/FAS-/FAS L -/BAX -/caspase-3-/ P53-/BCL2+).…”

Section: Discussionmentioning

confidence: 65%

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways

Khamis,

Abdelkhalek,

Abdellatif

et al. 2023

Front. Pharmacol.

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Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications.Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment.Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group.Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.

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Activating transcription factor 3 interferes with p21 activation in histone deacetylase inhibitor-induced growth inhibition of epidermoid carcinoma cells

Cited by 5 publications

References 31 publications

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Regulatory mechanisms of fluvastatin and lovastatin for the p21 induction in human cervical cancer HeLa cells

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways

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