Therapeutic Efficacy of <i>p53</i> Restoration in <i>Mdm2</i>-Overexpressing Tumors

Li, Qin; Zhang, Yun; El‐Naggar, Adel K.; Xiong, Shunbin; Yang, Peirong; Jackson, James G.; Chau, Gilda; Lozano, Guillermina

doi:10.1158/1541-7786.mcr-14-0089

Cited by 28 publications

(28 citation statements)

References 35 publications

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“…Our data suggest that in addition to p53 activation, Nutlin is also stabilizing Mdm2 causing an increase in the levels of Mdm2, which dampens the p53 response to DNA damage, resulting in increased sensitivity to genotoxic drugs (22,23). A small number of studies have also explored the effect Nutlin in combination with genotoxic drugs in cancer cells with mutated or deleted p53, but the mechanism for the observed cooperation between the two in this context was poorly understood.…”

Section: Discussionmentioning

confidence: 85%

Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells

Carrillo

Hicks

Khabele

et al. 2015

Molecular Cancer Research

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The Mdm2 oncogene is a negative regulator of the p53 tumor suppressor and recently identified inhibitor of DNA break repair. Nutlin-3 is a small molecule inhibitor of Mdm2/p53 interaction that can induce apoptosis in cancer cells through activation of p53. While this is promising therapy for those cancers with wild-type p53, half of all human cancers have inactivated p53. Here, we reveal a previously unappreciated effect of Nutlin is inhibition of DNA break repair, stemming from its ability to increase Mdm2 protein levels. The Nutlin-induced increase in Mdm2 inhibited DNA double-strand break (DSB) repair and prolonged DNA damage response signaling independent of p53. Mechanistically, this effect of Nutlin required Mdm2 and acted through Nbs1 of the Mre11/Rad50/Nbs1 DNA repair complex. In ovarian cancer cells where >90% have inactivated p53, Nutlin combined with the genotoxic agents, cisplatin or etoposide, had a cooperative lethal effect resulting in increased DNA damage and apoptosis. Therefore, these data demonstrate an unexpected consequence of pharmacologically increasing Mdm2 levels that when utilized in combination with genotoxic agents induces synthetic lethality in ovarian cancer cells, and likely other malignant cell types, that have inactivated p53. Implications Data reveal a therapeutically beneficial effect of pharmacologically increasing Mdm2 levels combined with chemotherapeutic agents for malignancies that have lost functional p53.

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Section: Discussionmentioning

confidence: 85%

Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells

Carrillo

Hicks

Khabele

et al. 2015

Molecular Cancer Research

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“…In contrast, recent data indicates that the ability of MDM2 to suppress wild type p53 varies greatly, and is highly dependent on the relative expression levels of the two genes (34). Indeed, MDM2 can even act as a growth suppressor under certain conditions (35).…”

Section: Discussionmentioning

confidence: 97%

Constitutive Activation of DNA Damage Checkpoint Signaling Contributes to Mutant p53 Accumulation via Modulation of p53 Ubiquitination

Frum

Love

Damle

et al. 2016

Molecular Cancer Research

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Many mutant p53 proteins exhibit an abnormally long half-life and overall increased abundance compared to wild-type p53 in tumors, contributing to mutant p53’s gain-of-function oncogenic properties. Here a novel mechanism is revealed for the maintenance of mutant p53 abundance in cancer that is dependent on DNA damage checkpoint activation. High level mutant p53 expression in lung cancer cells was associated with preferential p53 mono vs. polyubiquitination, suggesting a role for the ubiquitin/proteasome system in regulation of mutant p53 abundance in cancer cells. Interestingly, mutant p53 ubiquitination status was regulated by ATM activation and downstream phosphorylation of mutant p53 (serine 15), both in resting and genotoxin-treated lung cancer cells. Specifically, either inhibition of ATM with caffeine or mutation of p53 (serine 15 to alanine) restored MDM2-dependent polyubiquitination of otherwise monoubiquitinated mutant p53. Caffeine treatment rescued MDM2-dependent proteasome degradation of mutant p53 in cells exhibiting active DNA damage signaling, and ATM knockdown phenocopied the caffeine effect. Importantly, in cells analyzed individually by flow cytometry, p53 levels were highest in cells exhibiting the greatest levels of DNA damage response, and interference with DNA damage signaling preferentially decreased the relative percentage of cells in a population with the highest levels of mutant p53. These data demonstrate that active DNA damage signaling contributes to high levels of mutant p53 via modulation of ubiquitin/proteasome activity toward p53. Implication The ability of DNA damage checkpoint signaling to mediate accumulation of mutant p53 suggests that targeting this signaling pathway may provide therapeutic gain.

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“…Tumor cells have another way to block p53 by MDM2 amplification and thus do not require p53 mutations. Recently, there are anti‐MDM2 therapy that block the MDM2‐p53 interaction and thus reestablish wild type p53 activity …”

Section: Discussionmentioning

confidence: 99%

Cytohistological correlation, immunohistochemistry and Murine Double Minute Clone 2 amplification of pulmonary artery intimal sarcoma: A case report with review of literature

Harbhajanka

Dahoud

Michael

et al. 2018

Diagnostic Cytopathology

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Pulmonary artery intimal sarcoma is a rare aggressive intraluminal tumor often misdiagnosed as acute or chronic pulmonary thromboembolism due to its clinical presentation and radiological findings. Thus early diagnosis is very crucial and may improve patient outcome. There is limited literature on diagnosis of pulmonary artery sarcoma by endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA). Herein, we report a case of mass‐like lesion in the PA diagnosed on cytological material obtained by EBUS‐TBNA with rapid on‐site evaluation (ROSE). The aspirate showed pleomorphic malignant spindled cells arranged in loosely cohesive clusters. The intraluminal origin of PAIS was supported by radiographic findings. Subsequently, the patient received preoperative chemotherapy and underwent tumor resection with reconstruction. This report describes the cytomorphologic features of this rare intravascular tumor and demonstrates how limited cytological sample obtained from EBUS‐TBNA with ROSE can be triaged efficiently for ancillary studies like immunohistochemistry and MDM2 amplification, thus expediting the management.

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Therapeutic Efficacy of p53 Restoration in Mdm2-Overexpressing Tumors

Cited by 28 publications

References 35 publications

Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells

Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells

Constitutive Activation of DNA Damage Checkpoint Signaling Contributes to Mutant p53 Accumulation via Modulation of p53 Ubiquitination

Cytohistological correlation, immunohistochemistry and Murine Double Minute Clone 2 amplification of pulmonary artery intimal sarcoma: A case report with review of literature

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