Trisenox disrupts MDM2-DAXX-HAUSP complex and activates p53, cell cycle regulation and apoptosis in acute leukemia cells

Kumar, Sanjay; Brown, Andrea M.; Tchounwou, Paul B.

doi:10.18632/oncotarget.26025

Cited by 9 publications

(32 citation statements)

References 55 publications

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“…Similarly, our finding also shows that TX caused genotoxicity in mice APL liver tissue (2B[i-v]). Accumulating evidence suggests that the DNA damage signal is transmitted by protein kinase (ATM& ATR) and its residues phosphorylation leading to disruption of MDM2-DAXX-HAUSP complex and activation of p53 (12,15,35). Our findings show that TX-induced genotoxic damage was transmitted by reduced ATM and stimulated ATR expression along with phosphorylation of CHK1 residue at ser 345 residue in mice APL liver tissue (Fig.3A).…”

Section: Discussionsupporting

confidence: 50%

“…It has been reported that DNA damage disrupts MDM2-DAXX-HAUSP complex leading to activation of p53 and MDM2 degradation in many cancer cells (12,15,35). Our findings reveal that TX reduced MDM2 expression in a dose dependent fashion (Fig.4A&B[i-v]), leading to p53 activation in APL mice bone marrow cells.…”

Section: Tx Activates P53 In Apl Mice Bone Marrow Cellssupporting

confidence: 57%

“…TX interacts with TRIB3/ PML-RARα and eradicates APL [29]. Our laboratory has previously found that TX disrupted MDM2-DAXX-HAUSP complex, reduced expression of MDM2, and activated p53 in APL cell lines [35]. However, there is no previous report evaluating it effect on MDM2-DAXX-HAUSP complex in a mouse model of APL.…”

Section: Discussionmentioning

confidence: 94%

“…Trisenox inhibits the proliferation of APL cell lines through complex disruption, and MDM2 degradation leading to activation of p53. TX-induced p53 activation is involved in APL cell cycle modulation and apoptosis (35). TX-induced DNA damage signal transmission through protein kinase (ATM &ATR) led to the disruption of complex molecules and change in their association, p53 activation, cell cycle regulation, and forcing APL mice liver and bone marrow cells to undergo apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Trisenox Disrupts MDM2-DAXX-HAUSP Complex and Induces Apoptosis in a Mouse Model of Acute Leukemia

Kumar¹,

Tchounwou²

2020

J. Cancer

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Trisenox (TX) is successfully used for both de novo and relapsed acute promyelocytic leukemia (APL) treatment. Although TX toxicity to APL cells is mediated by oxidative stress, DNA damage, cell cycle arrest, and apoptosis, its mode of action in the transgenic mice model of APL is poorly understood. We hypothesized that TX regulates cell cycle and apoptosis in APL mice by p53 activation, DNA damage, and reduced expression of MDM2-DAXX-HAUSP complex. To test hypothesis, we treated APL mice with different doses (0, 1.25.2.5.5.0 & 7.5 mg/kg body wt) of TX and collected the liver and bone marrow cells. We applied several techniques to check the expression of PML-RARα, complex molecules, and DNA damage in APL mice bone marrow cells and liver. Our findings indicate that TX reduced the expression of PML-RARα and complex molecules, induced DNA damage and activated p53 leading to cell cycle arrest and apoptosis in APL mice liver. We found that TX promoted more promyelocytes formation with dense granules in bone marrow cells. It also transmitted the DNA damage signal through protein kinase (ATM & ATR) leading to disruption of complex and activation of p53 in APL mice liver. TX induced cell cycle arrest through activation of p53, p21, and reduced expression of cyclin D1 and cyclin dependent kinases (CDK 2, 4 & 6) in mice liver. It also caused apoptosis through upregulation of caspase 3 and Bax expression, and down-regulation of Bcl2 expression. Taken together, these molecular targets provide new insights into TX mode of action in APL mice.

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Section: Discussionsupporting

confidence: 50%

Section: Tx Activates P53 In Apl Mice Bone Marrow Cellssupporting

confidence: 57%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Trisenox Disrupts MDM2-DAXX-HAUSP Complex and Induces Apoptosis in a Mouse Model of Acute Leukemia

Kumar¹,

Tchounwou²

2020

J. Cancer

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“…In addition, we also found that endogenous DAXX mRNA expression was upregulated soon after exposure to UV irradiation; however, total protein levels were not elevated as expected, consistent with a microarray experiment showing that DAXX mRNA is upregulated in breast cancer cells upon exposure to curcumin relative to that in mammary epithelial cell lines 25 . Moreover, a previous study showed that DAXX is phosphorylated rapidly to induce p53 activation in response to DNA damage through the ataxia telangiectasia mutated(ATM)/Ataxia telangiectasia and Rad3 related (ATR) signaling pathway 26 . Therefore, we postulated that DAXX may play an intrinsic role in the DNA damage-induced response depending on the level of phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Enhanced UV Resistance Role of Death Domain–Associated Protein in Human MDA-MB-231 Breast Cancer Cells by Regulation of G2 DNA Damage Checkpoint

et al. 2020

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Purpose: Death domain–associated protein (DAXX) is a multifunctional nuclear protein involved in apoptosis, transcription, deoxyribonucleic acid damage response, and tumorigenesis. However, the role of DAXX in breast cancer development and progression remains elusive. In this study, we examined the expression patterns and function of DAXX in human breast cancer samples and cell lines. Methods: Immunohistochemistry was used to analyze the expression and localization patterns of DAXX. Additionally, we investigated whether DAXX played an intrinsic role in the cellular response to damage induced by ultraviolet (UV) irradiation in MDA-MB-231 breast cancer cells (isolated at M D Anderson from a pleural effusion of a patient with invasive ductal carcinoma). Results: Our results showed that nucleus size, chromatin organization, and DAXX localization were altered in breast cancer tissues compared with those in control tissues. Compared with cytoplasmic and nuclear expression in benign breast tissues, DAXX was colocalized with promyelocytic leukemia in nuclei with a granular distribution. Endogenous DAXX messenger ribonucleic acid levels were upregulated upon UV radiation in MDA-MB-231 cells. DAXX-deficient cells tended to be more sensitive to irradiation than control cells. Conversely, DAXX-overexpressing cells exhibited reduced phosphorylated histone H2AX (γ-H2AX) accumulation, increased cell survival, and resistance to UV-induced damage. The protective effects of DAXX may be related to the activation of the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (ATM-CHK2)-cell division cycle 25c (CDC25c) signaling pathways in Gap2/Mitosis (G2/M) checkpoint and ultimately cell cycle arrest at G2/M phase. Conclusions: Taken together, these results suggested that DAXX may be an essential component in breast cancer initiation, malignant progression, and radioresistance.

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Arsenic trioxide reduces the expression of E2F1, cyclin E, and phosphorylation of PI3K signaling molecules in acute leukemia cells

Kumar

Tchounwou

2021

Environmental Toxicology

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Arsenic trioxide (ATO) has been used for the treatment of acute promyelocytic leukemia (APL). Although ATO modulates cell cycle progression and apoptosis in APL cells, its exact mechanism of action remains elusive. In this research, we investigated its effects on E2F1, cyclin E, p53, pRb, and PI3K signaling molecules by western blotting, immunocytochemistry and/or confocal imaging. We found that ATO inhibited the proliferation of APL cells through down‐regulation of E2F1 and cyclin E expression, and stimulation of pRb. It also reduced the interaction of pRb and E2F1with binding to the E2F1 promoter, by stimulating pRb association. ATO also effected the phosphorylation of pRb at S608 and T373 residues and association of E2F1, pRb, and p53, simultaneously. However, in p53‐knockdown NB4 cells, ATO did not significantly reduce E2F1 and cyclin E expression. Our findings demonstrate that ATO inhibits APL cell growth through reduced expression of E2F1, cyclin E, and stimulation of pRb. It also effected both interaction and association of E2F1, pRb, and p53 by phosphorylation of pRb at T373 and S608 residues and reduced phosphorylation of PI3K signaling molecules. This novel mode of action of ATO in APL cells may be useful for designing new APL drugs.

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Trisenox disrupts MDM2-DAXX-HAUSP complex and activates p53, cell cycle regulation and apoptosis in acute leukemia cells

Cited by 9 publications

References 55 publications

Trisenox Disrupts MDM2-DAXX-HAUSP Complex and Induces Apoptosis in a Mouse Model of Acute Leukemia

Trisenox Disrupts MDM2-DAXX-HAUSP Complex and Induces Apoptosis in a Mouse Model of Acute Leukemia

Enhanced UV Resistance Role of Death Domain–Associated Protein in Human MDA-MB-231 Breast Cancer Cells by Regulation of G2 DNA Damage Checkpoint

Arsenic trioxide reduces the expression of E2F1, cyclin E, and phosphorylation of PI3K signaling molecules in acute leukemia cells

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