Activation of p53 and destabilization of androgen receptor by combinatorial inhibition of MDM2 and MDMX in prostate cancer cells

Chopra, Harman; Khan, Zara Ahmad; Contreras, J Diego; Wang, Herui; Sedrak, Abanob; Zhu, Yuyan

doi:10.18632/oncotarget.23569

Cited by 19 publications

(20 citation statements)

References 62 publications

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“…The rationale for this approach is that co-expression of MDM2 and MDM4 leads to stabilization of androgen receptor (AR) and further, that MDM4 modulates MDM2-mediated AR ubiquitination. At least in vitro , combined treatment activates p53 and destabilizes AR in prostate cancer cells (Chopra et al, 2018). Another compound with demonstrated potential in prostate cells to target the MDM2–MDM4 axis is the natural MDM2 inhibitor Inulanolide A (InuA).…”

Section: Mdm4 Therapeutics and As A Prognostic Biomarkermentioning

confidence: 99%

The long and the short of it: the MDM4 tail so far

Haupt

Mejía-Hernández

Vijayakumaran

et al. 2019

Journal of Molecular Cell Biology

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The mouse double minute 4 (MDM4) is emerging from the shadow of its more famous relative MDM2 and is starting to steal the limelight, largely due to its therapeutic possibilities. MDM4 is a vital regulator of the tumor suppressor p53. It restricts p53 transcriptional activity and also, at least in development, facilitates MDM2’s E3 ligase activity toward p53. These functions of MDM4 are critical for normal cell function and a proper response to stress. Their importance for proper cell maintenance and proliferation identifies them as a risk for deregulation associated with the uncontrolled growth of cancer. MDM4 tails are vital for its function, where its N-terminus transactivation domain engages p53 and its C-terminus RING domain binds to MDM2. In this review, we highlight recently identified cellular functions of MDM4 and survey emerging therapies directed to correcting its dysregulation in disease.

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Section: Mdm4 Therapeutics and As A Prognostic Biomarkermentioning

confidence: 99%

The long and the short of it: the MDM4 tail so far

Haupt

Mejía-Hernández

Vijayakumaran

et al. 2019

Journal of Molecular Cell Biology

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“…Kodacel flters were purchased from Unique Photo Inc. (Fairfeld, NJ), and UVR lamps from National Biologicals Corporation (Beachwood, OH). Mice were exposed to UVR in six solar lamp sets that filtered by Kodacel, and the methods was described as before (Chopra et al, ; Singh et al, ). The whole body of mice were continuously irradiated for about 20 weeks.…”

Section: Methodsmentioning

confidence: 99%

Retracted: Gadd45a gene silencing by RNAi promotes cell proliferation and inhibits apoptosis and senescence in skin squamous cell carcinoma through the p53 signaling pathway

Liu

Tian

Xiong

et al. 2018

Journal Cellular Physiology

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Skin squamous cell carcinoma (SCC) is generally considered as nonaggressive lesions and mainly caused by ultraviolet (UV) radiation. Gadd45a is a key component protecting skin against UV-induced tumors. For that, the study aims to investigate the mechanism of Gadd45a gene silencing on cell proliferation, apoptosis, and senescence in nude mice with skin SCC through the p53 signaling pathway. Healthy nude mice was collected as the normal group and 40 nude mouse models of skin SCC were successfully established as the model group, which were sub-divided into five groups. The incidence, size, and weight of SCC tumor of nude mice were observed. The mRNA expression of Gadd45a, Cyclin B1, MMP-2, Bcl-2, and Bax were determined by RT-qPCR. Cell viability, cell cycle and apoptosis, cell senescence were detected by MTT assay, flow cytometry, and β-galactosidase staining, respectively. The levels of inflammatory factors and vascular endothelial growth factor (VEGF) were detected by using ELISA. The protein expression rate of mutant p53 was detected by immunohistochemistry. Mice transfected with siGadd45a showed increased tumor incidence, size, and weight. Cells transfected with siGadd45a showed decrease in expression of Gadd45a and Bax; and increase in expression of Cyclin B1, MMP-2, and Bcl-2, expression of mutant p53, IL-1α, IL-1β, IL-6, TNF-α, and VEGF. Cell apoptosis and senescence were inhibited, while cell viability and proliferation were promoted after siGadd45a treatment. The results reveal that Gadd45a silencing increases tumor cell proliferation and reduces apoptosis and senescence through the p53 signaling pathway in skin SCC.

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“…PTEN, P53, MDM2 and AR dysregulation in human prostate cancer has been widely described [ 30 , 31 , 32 ]. PTEN and P53 downregulation plays an important role in cell growth and apoptosis [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the same cell phenotype may be involved in the development of both PIA and PC in dogs and both lesions may have a common origin in most-but not all-cases. PTEN, P53, MDM2 and AR dysregulation in human prostate cancer has been widely described [30][31][32]. PTEN and P53 downregulation plays an important role in cell growth and apoptosis [33].…”

Section: Discussionmentioning

confidence: 99%

Morphological and Molecular Characterization of Proliferative Inflammatory Atrophy in Canine Prostatic Samples

Fernandes

Pedrina

Lainetti

et al. 2021

Cancers

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Proliferative inflammatory atrophy (PIA) is an atrophic lesion of the prostate gland that occurs in men and dogs and is associated with a chronic inflammatory infiltrate. In this study, we retrospectively reviewed canine prostatic samples from intact dogs, identifying 50 normal prostates, 140 cases of prostatic hyperplasia, 171 cases of PIA, 84 with prostate cancer (PC), 14 with prostatic intraepithelial neoplasia (PIN) and 10 with bacterial prostatitis. PIA samples were then selected and classified according to the human classification. The presence of PIA lesions surrounding neoplastic areas was then evaluated to establish a morphological transition from normal to preneoplastic and neoplastic tissue. In addition, the expression of PTEN, P53, MDM2 and nuclear androgen receptor (AR) were analyzed in 20 normal samples and 20 PIA lesions by immunohistochemistry and qPCR. All PIA lesions showed variable degrees of mononuclear cell infiltration around the glands and simple atrophy was the most common histopathological feature. PIA was identified between normal glands and PC in 51 (61%) out of the 84 PC samples. PIA lesions were diffusely positive for molecular weight cytokeratin (HMWC). Decreased PTEN and AR gene and protein expression was found in PIA compared to normal samples. Overall, our results strongly suggest that PIA is a frequent lesion associated with PC. Additionally, this finding corroborates the hypothesis that in dogs, as is the case in humans, PIA is a pre neoplastic lesion that has the potential to progress into PC, indicating an alternative mechanism of prostate cancer development in dogs.

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Activation of p53 and destabilization of androgen receptor by combinatorial inhibition of MDM2 and MDMX in prostate cancer cells

Cited by 19 publications

References 62 publications

The long and the short of it: the MDM4 tail so far

The long and the short of it: the MDM4 tail so far

Retracted: Gadd45a gene silencing by RNAi promotes cell proliferation and inhibits apoptosis and senescence in skin squamous cell carcinoma through the p53 signaling pathway

Morphological and Molecular Characterization of Proliferative Inflammatory Atrophy in Canine Prostatic Samples

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