scholarly journals Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 969
Author(s):  
John S. Lazo ◽  
Elizabeth R. Sharlow ◽  
Robert Cornelison ◽  
Duncan J. Hart ◽  
Danielle C. Llaneza ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Migration ◽  
Tyrosine Phosphatase ◽  
In Vitro Cytotoxicity ◽  
Mrna Levels ◽  
High Grade ◽  
Drug Resistant ◽  
Ovca Cell

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053.

scholarly journals Clinical Value of lncRNA MEG3 in High-Grade Serous Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 966 ◽  
Author(s):  
Marianna Buttarelli ◽  
Marta De Donato ◽  
Giuseppina Raspaglio ◽  
Gabriele Babini ◽  
Alessandra Ciucci ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Biology ◽  
Tissue Level ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Clinical Value ◽  
Pre Treatment ◽  
Phosphatase And Tensin Homologue

Long non-coding RNAs (lncRNAs) are emerging as regulators in cancer development and progression, and aberrant lncRNA profiles have been reported in several cancers. Here, we evaluated the potential of using the maternally expressed gene 3 (MEG3) tissue level as a prognostic marker in high-grade serous ovarian cancer (HGSOC), the most common and deadliest gynecologic malignancy. To the aim of the study, we measured MEG3 transcript levels in 90 pre-treatment peritoneal biopsies. We also investigated MEG3 function in ovarian cancer biology. We found that high MEG3 expression was independently associated with better progression-free (p = 0.002) and overall survival (p = 0.01). In vitro and in vivo preclinical studies supported a role for MEG3 as a tumor suppressor in HGSOC, possibly through modulation of the phosphatase and tensin homologue (PTEN) network. Overall, results from this study demonstrated that decreased MEG3 is a hallmark for malignancy and tumor progression in HGSOC.

scholarly journals A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 662 ◽  
Author(s):  
Martyna Pakuła ◽  
Paweł Uruski ◽  
Arkadiusz Niklas ◽  
Aldona Woźniak ◽  
Dariusz Szpurek ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Specific Pattern ◽  
Laboratory Animals ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Mesenchymal Transition

The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal transition (MMT) elicited by these cells in normal peritoneal mesothelial cells (PMCs). Experiments were performed on primary PMCs, stable and primary ovarian cancer cells, tumors from patients with ovarian cancer, and laboratory animals. Results of in vitro and in vivo tests showed that MMT triggered by HGSOCs (primary cells and OVCAR-3 line) is far more pronounced than the process evoked by cells representing less aggressive ovarian cancer histotypes (A2780, SKOV-3). Mechanistically, HGSOCs induce MMT via Smad 2/3, ILK, TGF-β1, HGF, and IGF-1, whereas A2780 and SKOV-3 cells via exclusively Smad 2/3 and HGF. The conditioned medium from PMCs undergoing MMT promoted the progression of cancer cells and the effects exerted by the cells triggered to undergo MMT by the HGSOCs were significantly stronger than those related to the activity of their less aggressive counterparts. Our findings indicate that MMT in PMCs provoked by HGSOCs is stronger, proceeds via different mechanisms and has more procancerous characteristics than MMT provoked by less aggressive cancer histotypes, which may at least partly explain high aggressiveness of HGSOCs.

scholarly journals Cytotoxic capacity of a novel glycosylated antitumor ether lipid in chemotherapy-resistant high grade serous ovarian cancer in vitro and in vivo

2021 ◽  
Vol 14 (11) ◽  
pp. 101203
Author(s):  
Mark W Nachtigal ◽  
Paris Musaphir ◽  
Shiv Dhiman ◽  
Alon D Altman ◽  
Frank Schweizer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Ether Lipid ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1369
Author(s):  
Mikhail S. Chesnokov ◽  
Imran Khan ◽  
Yeonjung Park ◽  
Jessica Ezell ◽  
Geeta Mehta ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Ovarian Carcinoma ◽  
Cell Lines ◽  
Tumor Growth Rate ◽  
High Recurrence Rate ◽  
High Grade ◽  
Serous Ovarian Carcinoma

High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.

scholarly journals H3.3K27M Mutation Promotes The Migration and Invasion of Glioma Cells By Activating β-Catenin/USP1 Signaling

2022 ◽  
Author(s):  
Zhiyuan Sun ◽  
Yufu Zhu ◽  
Xia Feng ◽  
Xiaoyun Liu ◽  
Kunlin Zhou ◽  
...  
Keyword(s):  
Glioma Cells ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
High Grade ◽  
Protein Levels ◽  
Adult Glioma

Abstract H3.3K27M is a newly identified molecular pathology marker in glioma and is especially correlated with the malignancy of diffuse intrinsic pontine glioma (DIPG). In recent years, accumulating research has revealed that other types of glioma also contain the H3.3K27M mutation. However, the role of H3.3K27M in high-grade adult glioma, which is the most malignant glioma, has not been investigated. In this study, we focused on exploring the expression and function of H3.3K27M in high-grade adult glioma patients. We found that H3.3K27M is partly highly expressed in high-grade glioma tissues. Then, we introduced H3.3K27M into H3.3 wild-type glioma cells, U87 cells and LN229 cells. We found that H3.3K27M did not regulate the growth of glioma in vitro and in vivo; however, the survival of mice with transplanted tumors was significantly reduced. Further investigation revealed that H3.3K27M expression mainly promoted the migration and invasion of glioma cells. Moreover, we certified that H3.3K27M overexpression enhanced the protein levels of ꞵ-catenin and p-ꞵ-catenin, the protein and mRNA levels of ubiquitin-specific protease 1 (USP1), and the protein level of enhancer of zeste homolog 2 (EZH2). Importantly, the ꞵ-catenin inhibitor XAV-939 significantly attenuated the upregulation of the aforementioned proteins. Overall, the H3.3K27M mutation is present in a certain proportion of high-grade glioma patients and facilitates a poor prognosis by promoting the metastasis of glioma by regulating the ꞵ-catenin/USP1/EZH2 pathway.

scholarly journals Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5908
Author(s):  
Adam Neal ◽  
Tiffany Lai ◽  
Tanya Singh ◽  
Neela Rahseparian ◽  
Tristan Grogan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Ovarian Cancer Cell Lines ◽  
Poor Outcomes

Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs.

scholarly journals SIAH1-Mediated RPS3 Ubiquitination Contributes to Chemosensitivity in Epithelial Ovarian Cancer

2021 ◽  
Author(s):  
Lu Chen ◽  
Wujiang Gao ◽  
Chunli Sha ◽  
Taoqiong Li ◽  
Li Lin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Ectopic Expression ◽  
Ring Finger ◽  
Treatment Resistance ◽  
Mrna Levels ◽  
Protein Levels ◽  
Tumour Suppressor Function

Abstract Background: The E3 ligase SIAH1 is deregulated in human cancers and correlated with poor prognosis, but its contributions to chemoresistance in epithelial ovarian cancer (EOC) are not evident. Methods: SIAHI, RPS3, NF-κB (P65), FLAG and GFP protein levels were assessed by western blotting (WB) or immunohistochemistry (IHC). The mRNA levels were revealed by qRT-PCR. Colocalization of RPS3 and SIAH1 was detected by confocal microscopy and co-immunoprecipitation (CO-IP). RPS3 ubiquitination levels were detected by immunoprecipitation (IP). Cell functional experiments were performed and A2780 xenograft models were employed to expose the latent mechanisms of the SIAH1-RPS3-NF-κB axis as well as the role of SIAH1 in inhibiting chemoresistance in vitro and in vivo.Results: We show that SIAH1 is decreased in EOC tumour tissues and cell lines and negatively correlated with RPS3 level. SIAH1 overexpression suppresses tumour cell growth, colony formation, invasion, metastasis, and cisplatin resistance in vivo and in vitro. SIAH1 promoted RPS3 ubiquitination and degradation using the RING-finger domain, which was required for RPS3 localization to the cytoplasm for subsequent NF-κB inactivation, thereby conferring chemosensitivity. Moreover, ectopic expression of RPS3 or depletion of RPS3 ubiquitination mediated by SIAH1 via the K214R mutant significantly impaired cisplatin-induced tumour suppression in cells stably expressing SIAH1. Conclusions: Our findings reveal a tumour suppressor function of SIAH1 and provide evidence that the SIAH1-RPS3-NF-κB axis may act as an appealing strategy to tackle treatment resistance in EOC.

scholarly journals ATIM-22. PHASE I TRIAL OF DRUG RESISTANT IMMUNOTHERAPY: A FIRST-IN-CLASS COMBINATION OF MGMT-MODIFIEDγδ T CELLS AND TEMOZOLOMIDE CHEMOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi6-vi6
Author(s):  
Lawrence Lamb ◽  
James Markert ◽  
G Yancey Gillespie ◽  
Melissa Beelen ◽  
Catherine Langford ◽  
...  
Keyword(s):  
Phase I ◽  
Alkylating Agents ◽  
Single Agent ◽  
In Vitro Cytotoxicity ◽  
Drug Resistant ◽  
Term Survival ◽  
Treatment Frequency ◽  
Γδt Cells

Abstract INTRODUCTION Alkylating agents such as Temozolomide (TMZ) significantly upregulate stress-induced NKG2D ligands targeted by innate immune effector cells. Genetic modification of γδT cells with an MGMT-expressing lentivector abrogates TMZ-induced lymphodepletion allowing simultaneous chemotherapy and γδT cell therapy in a process we have termed Drug Resistant Immunotherapy (DRI) resulting in a significant improvement in long-term survival in patient-derived xenograft (PDXT) models of primary and recurrent GBM. We have now initiated a Phase I clinical trial of DRI in primary GBM (BB-IND-17928) to determine the safety of this approach. METHODS Effector γδT cells are manufactured from a fractional apheresis product obtained immediately prior to post-resection chemo/radiotherapy. Cultures are propagated in a Miltenyi Prodigy® bioreactor using media containing Zoledronic Acid and rhIL-12, transduced with a P140K-MGMT lentivector, maintained for up to 14 days, harvested, and cryopreserved. At the initiation of maintenance TMZ therapy, patients receive 150mg/m2 intravenous TMZ and 1 x 107 γδT cells delivered through a Rickham reservoir inserted into the tumor cavity at primary resection. Treatment frequency escalates from one to three 28-day cycles in a standard 3 x 3 design. RESULTS Closed system manufacturing in the Prodigy bioreactor produced 4.5 – 11.9 x 108 γδT cells (44–103 fold expansion) from the apheresis starting material (0.6–1.9% γδT cells) with vector copy numbers of 0.9 - 2.1 copies/cell and in vitro cytotoxicity against K562 44.3% - 77.9% at E:T 40:1. Products were successfully cryopreserved and retained in vivo potency against GBM PDXT in mice over single-agent TMZ (p= 0.0286). All cell products met sterility and identity criteria. CONCLUSIONS These findings show that genetically modified γδT cells can be manufactured to clinical scale under GMP compliance in an automated bioreactor and cryopreserved to produce multiple doses of functionally-competent γδT cells. Patient accrual will initiate in 2019.

scholarly journals NSun2 promotes cell migration through methylating autotaxin mRNA

2020 ◽  
Vol 295 (52) ◽  
pp. 18134-18147
Author(s):  
Xin Xu ◽  
Yihua Zhang ◽  
Junjie Zhang ◽  
Xiaotian Zhang
Keyword(s):  
Cell Migration ◽  
Biological Effects ◽  
Mrna Translation ◽  
Glioma Cell Line ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Protein Levels ◽  
Key Factor

NSun2 is an RNA methyltransferase introducing 5-methylcytosine into tRNAs, mRNAs, and noncoding RNAs, thereby influencing the levels or function of these RNAs. Autotaxin (ATX) is a secreted glycoprotein and is recognized as a key factor in converting lysophosphatidylcholine into lysophosphatidic acid (LPA). The ATX-LPA axis exerts multiple biological effects in cell survival, migration, proliferation, and differentiation. Here, we show that NSun2 is involved in the regulation of cell migration through methylating ATX mRNA. In the human glioma cell line U87, knockdown of NSun2 decreased ATX protein levels, whereas overexpression of NSun2 elevated ATX protein levels. However, neither overexpression nor knockdown of NSun2 altered ATX mRNA levels. Further studies revealed that NSun2 methylated the 3′-UTR of ATX mRNA at cytosine 2756 in vitro and in vivo. Methylation by NSun2 enhanced ATX mRNA translation. In addition, NSun2-mediated 5-methylcytosine methylation promoted the export of ATX mRNA from nucleus to cytoplasm in an ALYREF-dependent manner. Knockdown of NSun2 suppressed the migration of U87 cells, which was rescued by the addition of LPA. In summary, we identify NSun2-mediated methylation of ATX mRNA as a novel mechanism in the regulation of ATX.

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