Ironing out the role of the cyclin-dependent kinase inhibitor, p21 in cancer: Novel iron chelating agents to target p21 expression and activity

Moussa, Ronald; Park, Kyung Chan; Kovačević, Žaklina; Richardson, Des R.

doi:10.1016/j.freeradbiomed.2018.03.027

Cited by 28 publications

(27 citation statements)

References 304 publications

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“…Structural mitochondrial elements such as OPA1 and Drp1, responsible for mito-fusion or mito-fission respectively, regulate their activity according to iron level and they are directly involved, alongside p53 members, in the activation of the apoptotic signaling pathway [ 52 , 53 , 77 ]. The increased mitochondrial mass observed by confocal imaging showed a severe mitochondrial alteration in cells exposed to iron chelation, when compared to untreated cells, in line with the previously reported result [ 78 ]. The explanation for the mechanism could associated to an enhancement of the fusion process, through an inhibition of the fission process, or by a combination of both processes.…”

Section: Discussionsupporting

confidence: 91%

Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells

Calabrese

Panuzzo

Stanga

et al. 2020

IJMS

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Iron is crucial to satisfy several mitochondrial functions including energy metabolism and oxidative phosphorylation. Patients affected by Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) are frequently characterized by iron overload (IOL), due to continuous red blood cell (RBC) transfusions. This event impacts the overall survival (OS) and it is associated with increased mortality in lower-risk MDS patients. Accordingly, the oral iron chelator Deferasirox (DFX) has been reported to improve the OS and delay leukemic transformation. However, the molecular players and the biological mechanisms laying behind remain currently mostly undefined. The aim of this study has been to investigate the potential anti-leukemic effect of DFX, by functionally and molecularly analyzing its effects in three different leukemia cell lines, harboring or not p53 mutations, and in human primary cells derived from 15 MDS/AML patients. Our findings indicated that DFX can lead to apoptosis, impairment of cell growth only in a context of IOL, and can induce a significant alteration of mitochondria network, with a sharp reduction in mitochondrial activity. Moreover, through a remarkable reduction of Murine Double Minute 2 (MDM2), known to regulate the stability of p53 and p73 proteins, we observed an enhancement of p53 transcriptional activity after DFX. Interestingly, this iron depletion-triggered signaling is enabled by p73, in the absence of p53, or in the presence of a p53 mutant form. In conclusion, we propose a mechanism by which the increased p53 family transcriptional activity and protein stability could explain the potential benefits of iron chelation therapy in terms of improving OS and delaying leukemic transformation.

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Section: Discussionsupporting

confidence: 91%

Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells

Calabrese

Panuzzo

Stanga

et al. 2020

IJMS

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“…However, whether glutathione or sulfur metabolism is involved in SELENBP1-mediated induction of p21 protein warrants further investigation. The p21 protein, also known as p21 WAF1/CIP1 , is encoded by the CDKN1A gene mapped to chromosome 6p21.2, and belongs to the Cip/Kip family of CDK inhibitors [55]. A substantial number of studies have demonstrated p21 as a multifunctional, broad-acting protein that plays key roles in cell cycle regulation, cell migration and apoptosis [44].…”

Section: Discussionmentioning

confidence: 99%

Selenium-binding protein 1 transcriptionally activates p21 expression via p53-independent mechanism and its frequent reduction associates with poor prognosis in bladder cancer

et al. 2020

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Background: Recent studies have shown that selenium-binding protein 1 (SELENBP1) is significantly down-regulated in a variety of solid tumors. Nevertheless, the clinical relevance of SELENBP1 in human bladder cancer has not been described in any detail, and the molecular mechanism underlying its inhibitory role in cancer cell growth is largely unknown. Methods: SELENBP1 expression levels in tumor tissues and adjacent normal tissues were evaluated using immunoblotting assay. The association of SELENBP1 expression, clinicopathological features, and clinical outcome was determined using publicly available dataset from The Cancer Genome Atlas bladder cancer (TCGA-BLCA) cohort. DNA methylation in SELENBP1 gene was assessed using online MEXPRESS tool. We generated stable SELENBP1-overexpression and their corresponding control cell lines to determine its potential effect on cell cycle and transcriptional activity of p21 by using flow cytometry and luciferase reporter assay, respectively. The dominant-negative mutant constructs, TAM67 and STAT1 Y701F, were employed to define the roles of c-Jun and STAT1 in the regulation of p21 protein. Results: Here, we report that the reduction of SELENBP1 is a frequent event and significantly correlates with tumor progression as well as unfavorable prognosis in human bladder cancer. By utilizing TCGA-BLCA cohort, DNA hypermethylation, especially in gene body, is shown to be likely to account for the reduction of SELENBP1 expression. However, an apparent paradox is observed in its 3′-UTR region, in which DNA methylation is positively related to SELENBP1 expression. More importantly, we verify the growth inhibitory role for SELENBP1 in human bladder cancer, and further report a novel function for SELENBP1 in transcriptionally modulating p21 expression through a p53-independent mechanism. Instead, ectopic expression of SELENBP1 pronouncedly attenuates the phosphorylation of c-Jun and STAT1, both of which are indispensable for SELENBP1-mediated transcriptional induction of p21, thereby resulting in the G 0 /G 1 phase cell cycle arrest in bladder cancer cell.

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“…The cell cycle is strictly regulated by a complex network of events that promote or stop the progression of cells from one phase to the other (24). p21 plays a crucial role in cell cycle progression and cancer (24); it is able to mediate p53 activity and promote cell cycle arrest by inhibiting the activity and formation of cyclin/CDK complexes (24). At high levels, p21 inhibits the function of cdKs (25), thus inhibiting the cyclin D/CDK4/6 complex, resulting in G1/S arrest (26).…”

Section: Discussionmentioning

confidence: 99%

Phellinus�gilvus‑derived protocatechualdehyde induces G0/G1�phase arrest and apoptosis in murine B16‑F10 cells

Jin²,

et al. 2019

Mol Med Report

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Protocatechualdehyde (Pca) is considered to be the main phenolic component of Phellinus gilvus responsible for its anticancer properties. Previous studies have demonstrated that Pca can have an anticancer effect on multiple cancer types, but little is known about the effect of Pca on melanoma cells. The present study investigated the inhibitory abilities and potential anticancer mechanisms of Pca on B16-F10 cells using MTT assay. cell apoptosis and cell cycle were assessed by flow cytometry using Annexin V-FITC and propidium iodide staining. Whole-transcriptome analysis was used to investigate the effects of PCA on gene expression. PCA significantly decreased cell viability, induced cell cycle arrest at G0/G1 phase and promoted apoptosis of B16-F10 cells, suggesting that Pca could have anticancer effects against melanoma cells. Whole-transcriptome analysis indicated that Pca treatment upregulated genes involved in histone modification and decreased the transcription of genes involved in dna repair and replication. Kyoto encyclopedia of Genes and Genomes analysis showed that Pca treatment enhanced the complement and coagulation cascades, and the p53 signaling pathway. The present results indicated that Pca could act as an antitumor agent in melanoma cells, which may provide experimental support for the development of novel therapies to treat melanoma.

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Ironing out the role of the cyclin-dependent kinase inhibitor, p21 in cancer: Novel iron chelating agents to target p21 expression and activity

Cited by 28 publications

References 304 publications

Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells

Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells

Selenium-binding protein 1 transcriptionally activates p21 expression via p53-independent mechanism and its frequent reduction associates with poor prognosis in bladder cancer

Phellinus�gilvus‑derived protocatechualdehyde induces G0/G1�phase arrest and apoptosis in murine B16‑F10 cells

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