Targeting p53 for the treatment of cancer

Duffy, Michael J.; Synnott, Naoise C; O’Grady, Shane; Crown, John

doi:10.1016/j.semcancer.2020.07.005

Cited by 227 publications

(192 citation statements)

References 112 publications

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“…Combined with the result from the STRING database, we focused on the function of p53 at the follow-up study. It is known that tumor suppressor p53 involved in a variety of cellular events, for instance, p53/p21 signaling could induce cell cycle arrest and apoptosis as well as repress cell proliferation; oncogenes could promote MDM2-mediated degradation and ubiquitination of p53 [18][19][20][21][22][23][24][25][26][27][28][29]. In our study, we con rmed that the knockdown of PNO1 could increase luciferase activity by a p53-driven luciferase reporter assay and could enhance the protein levels of p53, CDKN1A (p21) and MDM2.…”

Section: Discussionsupporting

confidence: 59%

PNO1 promotes human cholangiocarcinoma tumorigenesis and chemosensitivity

Chen

Huang

et al. 2021

Preprint

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Background The partner of NOB1 homolog (PNO1) is important for ribosome biogenesis and serves as an oncogene in several cancers. However, the role of PNO1 in cholangiocarcinoma (CHOL) remains largely unknown. Methods The method of mRNA microarray analysis, high-throughput screening technologies, on-line databases analysis, PDXs models, biochemistry and molecular biology have been utilized to reveal the role of PNO1 in the progression of CHOL. Results PNO1 was significantly upregulated in CHOL tissues and predicted poor prognosis. PNO1 could induce cell proliferation and metastasis in vitro and in vivo. In CHOL cells expressing wild-type p53, PNO1 knockdown increased expression of p53 and its downstream gene p21 and decreased cell viability; these effects were blocked by p53 knockout and attenuated by the p53 inhibitor PFT-a. Furthermore, PNO1 knockdown reduced global protein synthesis and inhibiting MDM2-mediated ubiquitination and p53 degradation. Moreover, PNO1 overexpression enhanced the sensitivity to bortezomib treatment in CHOL. In addition, MYC overexpression promoted PNO1 promoter activity while MYC knockdown decreased PNO1 mRNA and protein, which led to decreased cell viability and clone formation. The expression of MYC was found positively correlated with PNO1 in CHOL patients. Conclusions Collectively, upregulation of PNO1 by MYC promotes cholangiocarcinoma tumorigenesis through suppressing p53 signaling pathway and enhanced the sensitivity to bortezomib treatment. PNO1 serves as a candidate of therapeutic target in CHOL treatment and clinical chemotherapy regimen.

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Section: Discussionsupporting

confidence: 59%

PNO1 promotes human cholangiocarcinoma tumorigenesis and chemosensitivity

Chen

Huang

et al. 2021

Preprint

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“…In this regard, identification and molecular charac- In fact, it has proved difficult to target tumor suppressors, such as p53, for cancer treatment because the development of reactivator drugs to recover the wild-type activity is much harder than designing drugs targeting cancer driver genes. 59 The same might be true for BACH2. Therefore, it requires new thinking or a different approach to target BACH2; for example, to target the downstream factors or cofactors of BACH2 instead.…”

Section: Discussionmentioning

confidence: 90%

“…In fact, it has proved difficult to target tumor suppressors, such as p53, for cancer treatment because the development of reactivator drugs to recover the wild‐type activity is much harder than designing drugs targeting cancer driver genes 59 . The same might be true for BACH2.…”

Section: Discussionmentioning

confidence: 99%

BACH2‐mediated FOS confers cytarabine resistance via stromal microenvironment alterations in pediatric ALL

Zhang

Zheng

et al. 2021

Cancer Science

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Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer that mainly affects children. Relapse and chemoresistance result in treatment failure, underlining the need for improved therapies. BTB and CNC homology 2 (BACH2) is a lymphoid‐specific transcription repressor recognized as a tumor suppressor in lymphomas, but little is known about its function and regulatory network in pediatric ALL (p‐ALL). Herein, we found aberrant BACH2 expression at new diagnosis not only facilitated risk stratification of p‐ALL but also served as a sensitive predictor of early treatment response and clinical outcome. Silencing BACH2 in ALL cells increased cell proliferation and accelerated cell cycle progression. BACH2 blockade also promoted cell adhesion to bone marrow stromal cells and conferred cytarabine (Ara‐C)–resistant properties to leukemia cells by altering stromal microenvironment. Strikingly, we identified FOS, a transcriptional activator competing with BACH2, as a novel downstream target repressed by BACH2. Blocking FOS by chemical compounds enhanced the effect of Ara‐C treatment in both primary p‐ALL cells and pre‐B‐ALL–driven leukemia xenografts and prolonged the survival of tumor‐bearing mice. These data highlight an interconnected network of BACH2‐FOS, disruption of which could render current chemotherapies more effective and offer a promising therapeutic strategy to overcome Ara‐C resistance in p‐ALL.

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“…The wild-type TP53 is a tumor suppressor that inhibits the proliferation and differentiation in cancer cells and regulates the G1 phase of the cell cycle. 45 When mutated or inactivated, p53 acts as an oncogene and promotes tumorigenesis. 46 The wild-type p53 protein is unstable and has a short half-life, and is therefore difficult to detect via immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

<p>Aptamer-Functionalized Dendrimer Delivery of Plasmid-Encoding lncRNA <em>MEG3</em> Enhances Gene Therapy in Castration-Resistant Prostate Cancer</p>

Tai¹,

Ma²,

Ding³

et al. 2020

IJN

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Purpose The clinical management of patients with castration-resistant prostate cancer (CRPC) is difficult. However, novel treatment methods are gradually being introduced. Considering the adverse effects of traditional treatments, recent studies have investigated gene therapy as a method to combat CRPC; but, the application of long non-coding (lnc) RNA in gene therapy remains scarce, despite their promise. Therefore, it is imperative to develop a system that can efficiently deliver lncRNA for the treatment of CRPC. Here, we investigated the efficacy of a delivery system by introducing the plasmid-encoding tumor suppressor lncRNA MEG3 (pMEG3) in CRPC cells. Materials and Methods An EpDT3 aptamer-linked poly(amidoamine) (PAMAM) dendrimer targeting EpCAM was used to deliver pMEG3 in CRPC cells. The PAMAM-PEG-EpDT3/pMEG3 nanoparticles (NPs) were tested using in vitro cellular assays including cellular uptake, entry, and CCK-8 measurement, and tumor growth inhibition, histological assessment, and safety evaluations in in vivo animal models. Results The EpDT3 aptamer promoted endocytosis of PAMAM and PAMAM-PEG-EpDT3/pMEG3 NPs in CRPC cells. PAMAM-PEG-EpDT3/pMEG3 NPs exhibited a significant anti-CRPC effect, both in vivo and in vitro, when compared to that of unfunctionalized PAMAM-PEG/pMEG3 NPs. Conclusion PAMAM-PEG-EpDT3/pMEG3 NPs can potentially improve gene therapy in CRPC cells.

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Targeting p53 for the treatment of cancer

Cited by 227 publications

References 112 publications

PNO1 promotes human cholangiocarcinoma tumorigenesis and chemosensitivity

PNO1 promotes human cholangiocarcinoma tumorigenesis and chemosensitivity

BACH2‐mediated FOS confers cytarabine resistance via stromal microenvironment alterations in pediatric ALL

<p>Aptamer-Functionalized Dendrimer Delivery of Plasmid-Encoding lncRNA <em>MEG3</em> Enhances Gene Therapy in Castration-Resistant Prostate Cancer</p>

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