scholarly journals STAT3 and p53: Dual Target for Cancer Therapy

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 637
Author(s):  
Thu-Huyen Pham ◽  
Hyo-Min Park ◽  
Jinju Kim ◽  
Jin Tae Hong ◽  
Do-Young Yoon
Keyword(s):  
Cancer Cell Proliferation ◽  
Tumor Suppressor P53 ◽  
Apoptotic Pathway ◽  
Cycle Arrest ◽  
Survival Pathway ◽  
Cancer Types ◽  
P53 Status ◽  
Pathway Regulation ◽  
The Guardian ◽  
The Relationship

The tumor suppressor p53 is considered the “guardian of the genome” that can protect cells against cancer by inducing cell cycle arrest followed by cell death. However, STAT3 is constitutively activated in several human cancers and plays crucial roles in promoting cancer cell proliferation and survival. Hence, STAT3 and p53 have opposing roles in cellular pathway regulation, as activation of STAT3 upregulates the survival pathway, whereas p53 triggers the apoptotic pathway. Constitutive activation of STAT3 and gain or loss of p53 function due to mutations are the most frequent events in numerous cancer types. Several studies have reported the association of STAT3 and/or p53 mutations with drug resistance in cancer treatment. This review discusses the relationship between STAT3 and p53 status in cancer, the molecular mechanism underlying the negative regulation of p53 by STAT3, and vice versa. Moreover, it underlines prospective therapies targeting both STAT3 and p53 to enhance chemotherapeutic outcomes.

scholarly journals Making Connections: p53 and the Cathepsin Proteases as Co-Regulators of Cancer and Apoptosis

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3476
Author(s):  
Surinder M. Soond ◽  
Lyudmila V. Savvateeva ◽  
Vladimir A. Makarov ◽  
Neonila V. Gorokhovets ◽  
Paul A. Townsend ◽  
...  
Keyword(s):  
Cell Death ◽  
P53 Protein ◽  
Genetic Locus ◽  
Signal Transduction Pathway ◽  
Tumor Suppressor P53 ◽  
Regulatory Relationship ◽  
Cathepsin Proteases ◽  
Recent Developments ◽  
Cancer Types ◽  
The Guardian

While viewed as the “guardian of the genome”, the importance of the tumor suppressor p53 protein has increasingly gained ever more recognition in modulating additional modes of action related to cell death. Slowly but surely, its importance has evolved from a mutated genetic locus heavily implicated in a wide array of cancer types to modulating lysosomal-mediated cell death either directly or indirectly through the transcriptional regulation of the key signal transduction pathway intermediates involved in this. As an important step in determining the fate of cells in response to cytotoxicity or during stress response, lysosomal-mediated cell death has also become strongly interwoven with the key components that give the lysosome functionality in the form of the cathepsin proteases. While a number of articles have been published highlighting the independent input of p53 or cathepsins to cellular homeostasis and disease progression, one key area that warrants further focus is the regulatory relationship that p53 and its isoforms share with such proteases in regulating lysosomal-mediated cell death. Herein, we review recent developments that have shaped this relationship and highlight key areas that need further exploration to aid novel therapeutic design and intervention strategies.

scholarly journals Genetic Networks Lead and Follow Tumor Development: MicroRNA Regulation of Cell Cycle and Apoptosis in the p53 Pathways

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Kurataka Otsuka ◽  
Takahiro Ochiya
Keyword(s):  
Cell Cycle ◽  
Tumor Development ◽  
Tumor Suppressor P53 ◽  
Microrna Regulation ◽  
Treatment And Prevention ◽  
Cycle Arrest ◽  
Regulation Of Cell Cycle ◽  
Tumor Types ◽  
The Guardian ◽  
Fine Tune

During the past ten years, microRNAs (miRNAs) have been shown to play a more significant role in the formation and progression of cancer diseases than previously thought. With an increase in reports about the dysregulation of miRNAs in diverse tumor types, it becomes more obvious that classic tumor-suppressive molecules enter deep into the world of miRNAs. Recently, it has been demonstrated that a typical tumor suppressor p53, known as the guardian of the genome, regulates some kinds of miRNAs to contribute to tumor suppression by the induction of cell-cycle arrest and apoptosis. Meanwhile, miRNAs directly/indirectly control the expression level and activity of p53 to fine-tune its functions or to render p53 inactive, indicating that the interplay between p53 and miRNA is overly complicated. The findings, along with current studies, will underline the continuing importance of understanding this interlocking control system for future therapeutic strategies in cancer treatment and prevention.

Deglucohellebrin: A Potent Agent for Glioblastoma Treatment

2020 ◽  
Vol 20 (1) ◽  
pp. 103-110
Author(s):  
Evrysthenis Vartholomatos ◽  
George A. Alexiou ◽  
Georgios S. Markopoulos ◽  
Diamanto Lazari ◽  
Olga Tsiftsoglou ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Primary Brain Tumor ◽  
Behavioral Alterations ◽  
Endemic Plant ◽  
M Cell ◽  
Apoptotic Pathway ◽  
Cycle Arrest ◽  
Dismal Prognosis ◽  
Mitochondrial Membrane Depolarization ◽  
Induced Changes

Background: Glioblastoma is the most common primary brain tumor in adults with a dismal prognosis. To date, several anticancer agents have been isolated from plants. Helleborus odorus subsp. Cyclophyllus is an endemic plant of the Balcan flora. Herewith, we investigated for the first time, the anti-glioma effect of deglucohellebrin (DGH) extracted from the roots of Helleborus. Methods: We investigated the effect of DGH in U251MG, T98G and U87G glioblastoma cell lines. We selected the T98G cells because of their inherent temozolomide resistance. Results: The IC50 value of reduced viability for DGH was 7x10-5M in U251MG cells, 5x10-5M for the T98G cells and 4x10-5M in U87G cells during 72h treatment. DGH induced G2/M cell cycle arrest, caspace-8 activation and significant mitochondrial membrane depolarization, suggesting the activation of the intrinsic, mitochondrial- dependent apoptotic pathway. DGH and temozolomide induced changes in CDs’ expression in U251MG and T98G cells. In zebrafish, DGH did not induce toxicity or behavioral alterations. Conclusion: The present study is the first to determine the anti-glioma activity of DGH. DGH may be a potent agent for glioblastoma treatment and further studies are needed.

scholarly journals The Anti-Tumor Activity of the NEDD8 Inhibitor Pevonedistat in Neuroblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6565
Author(s):  
Jennifer H. Foster ◽  
Eveline Barbieri ◽  
Linna Zhang ◽  
Kathleen A. Scorsone ◽  
Myrthala Moreno-Smith ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Wild Type ◽  
Tumor Weight ◽  
Cycle Arrest ◽  
P53 Status ◽  
Neuroblastoma Cell Lines ◽  
Anti Tumor Activity

Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin–RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromodeoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136–400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 status. Neuroblastoma cells with mutant (p53MUT) or reduced levels of wild-type p53 (p53si-p53) underwent G2-M cell-cycle arrest with rereplication, whereas p53 wild-type (p53WT) cell lines underwent G0-G1 cell-cycle arrest and apoptosis. In orthotopic neuroblastoma models, pevonedistat decreased tumor weight independent of p53 status. Control mice had an average tumor weight of 1.6 mg + 0.8 mg versus 0.5 mg + 0.4 mg (p < 0.05) in mice treated with pevonedistat. The mechanism of action of pevonedistat in neuroblastoma cell lines in vitro appears p53 dependent. However, in vivo studies using mouse neuroblastoma orthotopic models showed a significant decrease in tumor weight following pevonedistat treatment independent of the p53 status. Novel chemotherapy agents, such as the NEDD8-activating enzyme (NAE) inhibitor pevonedistat, deserve further study in the treatment of neuroblastoma.

scholarly journals Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 167
Author(s):  
Ting Su ◽  
Xian-Yang Qin ◽  
Naoshi Dohmae ◽  
Feifei Wei ◽  
Yutaka Furutani ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Cancer Cell Proliferation ◽  
Mitotic Progression ◽  
Cycle Arrest ◽  
Persistent Inflammation ◽  
Promising Target ◽  
Mechanistic Analysis ◽  
Incidence And Mortality ◽  
Dependent Cell ◽  
Lifestyle Diseases

The incidence and mortality of liver cancer, mostly hepatocellular carcinoma (HCC), have increased during the last two decades, partly due to persistent inflammation in the lipid-rich microenvironment associated with lifestyle diseases, such as obesity. Gangliosides are sialic acid-containing glycosphingolipids known to be important in the organization of the membrane and membrane protein-mediated signal transduction. Ganglioside synthesis is increased in several types of cancers and has been proposed as a promising target for cancer therapy. Here, we provide evidence that ganglioside synthesis was increased in the livers of an animal model recapitulating the features of activation and expansion of liver progenitor-like cells and liver cancer (stem) cells. Chemical inhibition of ganglioside synthesis functionally suppressed proliferation and sphere growth of liver cancer cells, but had no impact on apoptotic and necrotic cell death. Proteome-based mechanistic analysis revealed that inhibition of ganglioside synthesis downregulated the expression of AURKA, AURKB, TTK, and NDC80 involved in the regulation of kinetochore metaphase signaling, which is essential for chromosome segregation and mitotic progression and probably under the control of activation of TP53-dependent cell cycle arrest. These data suggest that targeting ganglioside synthesis holds promise for the development of novel preventive/therapeutic strategies for HCC treatment.

Prognostic Effects of Neutrophil-Lymphocyte Rates in Serum and Pleural Fluids in Malignant Pleural Fluids

2021 ◽  
Author(s):  
Filiz Güldaval ◽  
Ceyda Anar ◽  
Mine Gayaf ◽  
Gulru Polat ◽  
Merve Ayık Türk ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Prognostic Factor ◽  
Eastern Cooperative Oncology Group ◽  
Cost Effective ◽  
Clinical Impact ◽  
Neutrophil To Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Appropriate Therapy ◽  
Cancer Types ◽  
The Relationship

Objective: Various studies have reported that the neutrophil-to-lymphocyte ratio in the serum (sNLR) may serve as a cost-effective and useful prognostic factor in patients with various cancer types. We investigated the clinical impact of NLR as a prognostic factor in malign pleural effusion (MPE) and sNLR on prognosis in MPE. Method: We retrospectively reviewed all of the patients who were diagnosed MPE. The relationship between sNLR and neutrophil-to-lymphocyte ratio in the malign pleural effusion (mNLR) value, age, Eastern Cooperative Oncology Group (ECOG), histopathologic type, serum albumin and lactate dehydrogenase (LDH) with survival were investigated. Results: A total of 222 patients with a mean age of 65.7±11.5 were included in the study. Patients with a mNLR value ≥0.42 and a serum NLR value ≥4.75 had a shorter survival (p: 0.000). Multivariate analysis, which showed that survival was significantly related mNLR value > 0.42 and/or sNLR value > 4.75 (Odds Ratio (OR): 2.66, %95 CI, 1,65-4,3 p: 0.001), serum LDH > 210 (OR = 1.8, %95 CI, 1,33-2,46 p: 0.001) and age > 65 (OR = 1.9, %95 CI, 1,41-2,55 p = 0.001). Conclusion: sNLR and mNLR may act as a simple, useful, and cost-effective prognostic factor in patients with MPE. Furthermore, these results may serve as the cornerstone of further research into the mNLR in the future. Although further studies are required to generalize our results, this information will benefit clinicians and patients in determining the most appropriate therapy for patients with MPE.

EXTH-55. TARGETING RECURRENT IDH MUTANT GLIOMA WITH CDK4/6 INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi175-vi175
Author(s):  
Julie Miller ◽  
Daniel Cahill ◽  
Lisa Melamed ◽  
Hiroaki Nagashima
Keyword(s):  
Gene Deletion ◽  
Homozygous Deletion ◽  
Therapeutic Strategies ◽  
Enhanced Sensitivity ◽  
Rb Pathway ◽  
Cancer Types ◽  
Xenograft Models ◽  
The Relationship ◽  
Inhibitor Treatment

Abstract Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressively and lead to untimely death. Recurrent IDH mutant tumors are less responsive to conventional treatments, highlighting the need for improved therapeutic strategies at this stage of the disease. At least 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, which results in aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors, which are approved for use in a variety of other cancer types. We examined the relationship between CDK4/6 inhibitor sensitivity and CDKN2A loss using patient-derived models of IDH mutant glioma with endogenous CDKN2A homozygous deletion as well as with CRIPSR-mediated gene deletion. We observed enhanced cytotoxicity in glioma models with CDKN2A loss in vitro. Studies to examine the efficacy of CDK4/6 inhibitor treatment on slowing tumor growth in patient-derived xenograft models are ongoing. These preclinical results provide foundational data for design of a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.

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