Inhibition of BMI-1 Induces Apoptosis through Downregulation of DUB3-Mediated Mcl-1 Stabilization

Wu, Kaixin; Woo, Seon-Min; Seo, Seung-Un; Kwon, Taeg Kyu

doi:10.3390/ijms221810107

Cited by 6 publications

(5 citation statements)

References 35 publications

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“…The current study is in agreement with previous research that indicated that Akt/GSK3β signaling is required for MCL-1 S159 phosphorylation and degradation [48]. Certain deubiquitinases such as USP9X [49], JOSD1 [50], USP13 [51], DUB3 [52] and Ku70 [53] have been demonstrated to stabilize MCL-1. However, the molecular mechanisms by which these deubiquitinases stabilize MCL-1 are not fully understood.…”

Section: Discussionsupporting

confidence: 93%

Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance

Gao

et al. 2022

Cell Death Dis

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The E3 ligase TNF receptor-associated factor 4 (TRAF4) is frequently overexpressed and closely related to poor prognosis in human malignancies. However, its effect on carcinogenesis and radiosensitivity in oral squamous cell carcinoma (OSCC) remains unclear. The present study found that TRAF4 was significantly upregulated in primary and relapsed OSCC tumor tissues. Depletion of TRAF4 markedly improved the sensitivity of OSCC cells to irradiation (IR) treatment, showing that tumor cell proliferation, colony formation and xenograft tumor growth were reduced. Mechanistically, IR promoted the interaction between TRAF4 and Akt to induce Akt K63-mediated ubiquitination and activation. TRAF4 knockout inhibited the phosphorylation of Akt and upregulated GSK3β activity, resulting in increased myeloid cell leukemia-1 (MCL-1) S159 phosphorylation, which disrupted the interaction of MCL-1 with Josephin domain containing 1 (JOSD1), and ultimately induced MCL-1 ubiquitination and degradation. Moreover, TRAF4 was positively correlated with MCL-1 in primary and in radiotherapy-treated, relapsed tumor tissues. An MCL-1 inhibitor overcame radioresistance in vitro and in vivo. Altogether, the present findings suggest that TRAF4 confers radioresistance in OSCC by stabilizing MCL-1 through Akt signaling, and that targeting TRAF4 may be a promising therapeutic strategy to overcome radioresistance in OSCC.

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Section: Discussionsupporting

confidence: 93%

Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance

Gao

et al. 2022

Cell Death Dis

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“…With regard to the effect of PRIMA-1 MET , our results are in line with the study by Patyka M et al, reporting that the drug is effective in preventing the propagation of neurospheres originating from patientderived glioblastoma cells [84]. Similarly, this ability has been also recently described for PTC596 [87,88], suggesting that the modulation of BMI-1 might be a promising approach to curing cancer patients.…”

Section: Discussionsupporting

confidence: 91%

PTC596-Induced BMI-1 Inhibition Fights Neuroblastoma Multidrug Resistance by Inducing Ferroptosis

Valenti,

Roveri,

Venerando

et al. 2023

Antioxidants

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Neuroblastoma (NB) is a paediatric cancer with noteworthy heterogeneity ranging from spontaneous regression to high-risk forms that are characterised by cancer relapse and the acquisition of drug resistance. The most-used anticancer drugs exert their cytotoxic effect by inducing oxidative stress, and long-term therapy has been demonstrated to cause chemoresistance by enhancing the antioxidant response of NB cells. Taking advantage of an in vitro model of multidrug-resistant (MDR) NB cells, characterised by high levels of glutathione (GSH), the overexpression of the oncoprotein BMI-1, and the presence of a mutant P53 protein, we investigated a new potential strategy to fight chemoresistance. Our results show that PTC596, an inhibitor of BMI-1, exerted a high cytotoxic effect on MDR NB cells, while PRIMA-1MET, a compound able to reactivate mutant P53, had no effect on the viability of MDR cells. Furthermore, both PTC596 and PRIMA-1MET markedly reduced the expression of epithelial–mesenchymal transition proteins and limited the clonogenic potential and the cancer stemness of MDR cells. Of particular interest is the observation that PTC596, alone or in combination with PRIMA-1MET and etoposide, significantly reduced GSH levels, increased peroxide production, stimulated lipid peroxidation, and induced ferroptosis. Therefore, these findings suggest that PTC596, by inhibiting BMI-1 and triggering ferroptosis, could be a promising approach to fight chemoresistance.

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“…Inhibition of Bmi-1 can promote the expression of p14 ARF ( p19 ARF ), and p14 ARF (p19 ARF ) can antagonize the ubiquitin-protein ligase MDM2 to stabilize p53 and cause apoptosis. This phenomenon has been reported in many studies [ 29 , 96 , 97 ]. A second pathway involves the inhibition of Bmi-1, causing abnormal mitochondrial function and increasing the level of ROS, leading to apoptosis.…”

Section: Bmi-1-targeted Processes In Cancersupporting

confidence: 71%

The Crucial Roles of Bmi-1 in Cancer: Implications in Pathogenesis, Metastasis, Drug Resistance, and Targeted Therapies

Shi

et al. 2022

IJMS

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B-cell-specific Moloney murine leukemia virus integration region 1 (Bmi-1, also known as RNF51 or PCGF4) is one of the important members of the PcG gene family, and is involved in regulating cell proliferation, differentiation and senescence, and maintaining the self-renewal of stem cells. Many studies in recent years have emphasized the role of Bmi-1 in the occurrence and development of tumors. In fact, Bmi-1 has multiple functions in cancer biology and is closely related to many classical molecules, including Akt, c-MYC, Pten, etc. This review summarizes the regulatory mechanisms of Bmi-1 in multiple pathways, and the interaction of Bmi-1 with noncoding RNAs. In particular, we focus on the pathological processes of Bmi-1 in cancer, and explore the clinical relevance of Bmi-1 in cancer biomarkers and prognosis, as well as its implications for chemoresistance and radioresistance. In conclusion, we summarize the role of Bmi-1 in tumor progression, reveal the pathophysiological process and molecular mechanism of Bmi-1 in tumors, and provide useful information for tumor diagnosis, treatment, and prognosis.

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Inhibition of BMI-1 Induces Apoptosis through Downregulation of DUB3-Mediated Mcl-1 Stabilization

Cited by 6 publications

References 35 publications

Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance

Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance

PTC596-Induced BMI-1 Inhibition Fights Neuroblastoma Multidrug Resistance by Inducing Ferroptosis

The Crucial Roles of Bmi-1 in Cancer: Implications in Pathogenesis, Metastasis, Drug Resistance, and Targeted Therapies

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