scholarly journals MLK3 Is Associated With Poor Prognosis in Patients With Glioblastomas and Actin Cytoskeleton Remodeling in Glioblastoma Cells

2021 ◽  
Vol 10 ◽  
Author(s):  
Yan Zhu ◽  
Jin-Min Sun ◽  
Zi-Chen Sun ◽  
Feng-Jiao Chen ◽  
Yong-Ping Wu ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Poor Prognosis ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Recurrent Glioblastoma ◽  
Migration And Invasion ◽  
Breast Cancers ◽  
Recurrent Glioblastoma Multiforme ◽  
Genetic Ablation ◽  
Cytoskeleton Organization

Mixed lineage kinase 3 (MLK3) has been implicated in human melanoma and breast cancers. However, the clinical significance of MLK3 in human gliomas and the underlying cellular and molecular mechanisms remain unclear. We found that MLK3 proteins were highly expressed in high-grade human glioma specimens and especially prevalent in primary and recurrent glioblastoma multiforme (GBM). High levels of MLK3 mRNA were correlated with poor prognosis in patients with isocitrate dehydrogenase (IDH)-wild-type (wt) gliomas. Furthermore, genetic ablation of MLK3 significantly suppressed the migration and invasion abilities of GBM cells and disrupted actin cytoskeleton organization. Importantly, MLK3 directly bound to epidermal growth factor receptor kinase substrate 8 (EPS8) and regulated the cellular location of EPS8, which is essential for actin cytoskeleton rearrangement. Overall, these findings provide evidence that MLK3 upregulation predicts progression and poor prognosis in human IDH-wt gliomas and suggest that MLK3 promotes the migration and invasion of GBM cells by remodeling the actin cytoskeleton via MLK3-EPS8 signaling.

Phase II trial of high dose imatinib in recurrent glioblastoma multiforme (GBM) with platelet derived growth factor receptor (PDGFR) expression

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2056-2056 ◽  
Author(s):  
F. S. Viola ◽  
A. Katz ◽  
A. Arantes ◽  
A. Gaiger ◽  
C. Vasconcellos ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Significant Proportion ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
Recurrent Glioblastoma ◽  
High Dose ◽  
Recurrent Glioblastoma Multiforme ◽  
Disease Stabilization ◽  
Ecog Ps

2056 Background: GBM are the most common primary brain tumors in adults. Despite available treatment they carry a poor prognosis with recurrences in most patients (pts) after initial therapy. PDGF signaling has been postulated to play a role in GBM transformation. We have demonstrated that PDGFRβ is expressed in tumor cells in 50% and in peritumoral endothelial cells in 65% of GBM (Barrios et al, abstract 11518, Proc ASCO 2006). Imatinib, an inhibitor of PDGFRa/β kinase activity could have therapeutic activity in these cases. Methods: We evaluated Imatinib in pts with recurrent GBM (previous radiation and chemotherapy) selected by PDGFR expression. Analysis of PDGFRa/β was performed by standard IHC. Positivity was considered in case of any qualitative expression. Pts were treated with 800 mg/day of Imatinib until tumor progression. All were on steroids and taking enzyme inducing antiepileptic drugs. Response was determined by MRI with spectroscopy and perfusion every 8 weeks according to RECIST criteria. Results: Twenty pts were enrolled (18 GBM, 2 AA). Median age: 51 (21–74), 7 were females. ECOG-PS at inclusion: 0 (3), 1 (10), 2 (7). All pts had expression of PDGFRa and 55% expressed PDGFRβ. Response data are available for all 20 pts. Main adverse events (all grade 1–2) were: edema (55%), nausea (50%), diarrhea and fatigue (35% each). We did not observe any PR but 13 pts (65%) showed disease stabilization. Median progression-free survival was 7.8 months with 60.8% of pts alive at 6 months; 6 months PFS was 52.2%. Conclusions: Imatinib was well tolerated in this group of poor prognosis highly pre-treated GBM pts demonstrating disease stabilization in a significant proportion of cases. These results, in a limited sample, compare favorably with historical data in similar populations. Selection of pts according to the specific molecular expression of their tumor may lead to better therapeutic results. No significant financial relationships to disclose.

scholarly journals Bioactive Ent-Kaurane Diterpenes Oridonin and Irudonin Prevent Cancer Cells Migration by Interacting with the Actin Cytoskeleton Controller Ezrin

2020 ◽  
Vol 21 (19) ◽  
pp. 7186
Author(s):  
Valentina Pagliara ◽  
Giuliana Donadio ◽  
Nunziatina De Tommasi ◽  
Giuseppina Amodio ◽  
Paolo Remondelli ◽  
...  
Keyword(s):  
Cell Migration ◽  
Actin Cytoskeleton ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Experimental Models ◽  
Cytoskeletal Proteins ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Cytoskeleton Organization ◽  
Proteomic Approach

The ent-kaurane diterpene oridonin was reported to inhibit cell migration and invasion in several experimental models. However, the process by which this molecule exerts its anti-metastatic action has not been yet elucidated. In this article, we have investigated the anti-metastatic activity of Oridonin and of one homolog, Irudonin, with the aim to shed light on the molecular mechanisms underlying the biological activity of these ent-kaurane diterpenes. Cell-based experiments revealed that both compounds are able to affect differentiation and cytoskeleton organization in mouse differentiating myoblasts, but also to impair migration, invasion and colony formation ability of two different metastatic cell lines. Using a compound-centric proteomic approach, we identified some potential targets of the two bioactive compounds among cytoskeletal proteins. Among them, Ezrin, a protein involved in the actin cytoskeleton organization, was further investigated. Our results confirmed the pivotal role of Ezrin in regulating cell migration and invasion, and indicate this protein as a potential target for new anti-cancer therapeutic approaches. The interesting activity profile, the good selectivity towards cancer cells, and the lower toxicity with respect to Oridonin, all suggest that Irudonin is a very promising anti-metastatic agent.

scholarly journals Current Approaches and Emerging Directions in HER2-resistant Breast Cancer

2014 ◽  
Vol 8 ◽  
pp. BCBCR.S9453 ◽  
Author(s):  
Adam M. Brufsky
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Initial Response ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Intrinsic Resistance ◽  
Her2 Positive

Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancers; HER2 overexpression is indicative of poor prognosis. Trastuzumab, an anti-HER2 monoclonal antibody, has led to improved outcomes in patients with HER2-positive breast cancer, including improved overall survival in adjuvant and first-line settings. However, a large proportion of patients with breast cancer have intrinsic resistance to HER2-targeted therapies, and nearly all become resistant to therapy after initial response. Elucidation of underlying mechanisms contributing to HER2 resistance has led to development of novel therapeutic strategies, including those targeting HER2 and downstream pathways, heat shock protein 90, telomerase, and vascular endothelial growth factor inhibitors. Numerous clinical trials are ongoing or completed, including phase 3 data for the mammalian target of rapamycin inhibitor everolimus in patients with HER2-resistant breast cancer. This review considers the molecular mechanisms associated with HER2 resistance and evaluates the evidence for use of evolving strategies in patients with HER2-resistant breast cancer.

scholarly journals Prognostic values of L-type amino acid transporter 1 and CD98hc expression in breast cancer

2020 ◽  
pp. jclinpath-2020-206457
Author(s):  
Masaaki Ichinoe ◽  
Tetuo Mikami ◽  
Nobuyuki Yanagisawa ◽  
Tsutomu Yoshida ◽  
Kiyomi Hana ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Amino Acid ◽  
Invasive Breast Cancer ◽  
Poor Prognosis ◽  
Growth Factor Receptor ◽  
Amino Acid Transporter ◽  
Breast Cancers ◽  
Non Invasive ◽  
Invasive Tumour ◽  
Acid Transporter

AimsL-type amino acid transporter 1 (LAT1) is a major Na+-independent neutral amino acid transporter, forming a complex with CD98hc. The aim of this study is to investigate the significance of LAT1 and CD98hc in invasive breast cancer.MethodsLAT1 and CD98hc expression was immunohistochemically assessed in 280 invasive breast cancers and analysed for association with clinicopathological features.ResultsHigh levels of LAT1 and CD98hc were observed in triple-negative breast cancers (TNBCs) possessing negative immunoreactivity with oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, compared with non-TNBCs (NTNBCs), and were associated with lymph-node metastasis and higher nuclear grade. The high-LAT1-expression group showed a poor prognosis in NTNBC and TNBC, however, high-CD98hc-expression group showed a poor prognosis only in NTNBC. LAT1 and CD98hc expression could be the prognostic factors in univariate analyses, but not in multivariate analyses. Further, we found that invasive tumour components showed higher LAT1 and CD98hc expression than non-invasive tumour components.ConclusionsLAT1 and CD98hc may possess prognostic values in invasive breast cancer. LAT1 may be linked with cancer cell activities and disease progression in breast cancer.

A stratified phase II study of cetuximab for the treatment of recurrent glioblastoma multiforme: Preliminary results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1558-1558 ◽  
Author(s):  
J. Sadones ◽  
C. Chaskis ◽  
E. J. Joosens ◽  
L. A. Dhondt ◽  
J. Baurain ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Gene Copy Number ◽  
Growth Factor Receptor ◽  
Recurrent Glioblastoma ◽  
Gene Copy ◽  
Recurrent Glioblastoma Multiforme ◽  
Egfr Gene ◽  
Recurrent Gbm

1558 Background: The Epidermal Growth Factor Receptor (EGFR) gene is frequently amplified and mutated in high-grade gliomas. We are investigating the activity of the EGFR-targeted monoclonal antibody cetuximab for the treatment of patients (pts) with recurrent glioblastoma multiforme (GBM) following surgery, radiotherapy and chemotherapy. Methods: Adult pts with recurrent GBM are allocated to two parallel treatment strata according to the amplification status of the EGFR gene (determined by FISH). According to a Simon two-stage phase II study design 1 response in 13 pts/stratum is required to continue recruitment and complete the second stage of pt recruitment. Cetuximab is administered at 400 mg/m2 (2 hour infusion) day 1 and 250 mg/m2 day 8 and for all subsequent weekly doses (1 hour infusion). Results: Between May and December 2005, 17 pts were recruited (10 without EGFR-ampl, 4 with EGFR-ampl and 3 under investigation); 4F/13M; median age 51 years, range 32–67). Recruitment is ongoing. Sixteen pts initiated study treatment; 1 pt withdrew consent before the initiation of therapy. Treatment related toxicity in the first 94 treatment cycles consisted of grade 1/2 folliculitis/dermitis in all treated pts. Grade 3 adverse events consisted of thrombocytopenia (n=1 pt), diminished consciousness (n=1 pt), dizziness/confusion (n=1 pt), infectious bronchopneumonia (n=1 pt), and infectious cellulitis (n=1 pt). Thirteen pts have been evaluated for response ≤ week 8 of study treatment. Eleven pts had progression of disease. Two patients had SD at 8 weeks (follow-up is ongoing). Conclusions: These preliminary data suggest that cetuximab can be safely administered to pretreated patients with recurrent GBM. Updated results regarding safety and activity as well as a correlative study of EGFR and PTEN expression and gene copy number of the GBM and response to cetuximab will be presented at the meeting. No significant financial relationships to disclose.

scholarly journals High TRAF6 Expression Is Associated With Esophageal Carcinoma Recurrence and Prompts Cancer Cell Invasion

2017 ◽  
Vol 25 (4) ◽  
pp. 485-493 ◽  
Author(s):  
Xinyang Liu ◽  
Zhichao Wang ◽  
Guoliang Zhang ◽  
Qikun Zhu ◽  
Hui Zeng ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Molecular Mechanisms ◽  
Tumor Necrosis Factor Receptor ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Underlying Mechanisms ◽  
Patient Prognosis ◽  
Cancer Tissues

Esophageal cancer is one of the most common types of cancer, and it has a poor prognosis. The molecular mechanisms of esophageal cancer progression remain largely unknown. In this study, we aimed to investigate the clinical significance and biological function of tumor necrosis factor receptor-associated factor 6 (TRAF6) in esophageal cancer. Expression of TRAF6 in esophageal cancer was examined, and its correlation with clinicopathological factors and patient prognosis was analyzed. A series of functional and mechanism assays were performed to further investigate the function and underlying mechanisms in esophageal cancer. Expression of TRAF6 was highly elevated in esophageal cancer tissues, and patients with high TRAF6 expression have a significantly shorter survival time than those with low TRAF6 expression. Furthermore, loss-of-function experiments showed that knockdown of TRAF6 significantly reduced the migration and invasion abilities of esophageal cancer cells. Moreover, the pro-oncogenic effects of TRAF6 in esophageal cancer were mediated by the upregulation of AEP and MMP2. Altogether, our data suggest that high expression of TRAF6 is significant for esophageal cancer progression, and TRAF6 indicates poor prognosis in esophageal cancer patients, which might be a novel prognostic biomarker or potential therapeutic target in esophageal cancer.

scholarly journals The beta-tubulin isotype TUBB6 controls microtubule and actin dynamics in osteoclasts.

2021 ◽  
Author(s):  
Justine Maurin ◽  
Anne Morel ◽  
David Guérit ◽  
Julien Cau ◽  
Serge Urbach ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Actin Cytoskeleton ◽  
Molecular Mechanisms ◽  
Life Time ◽  
Negative Regulator ◽  
Actin Dynamics ◽  
Growth Speed ◽  
Actin Organization ◽  
Cytoskeleton Organization ◽  
Tubulin Isotype

Osteoclasts are bone resorbing cells that participate in the maintenance of bone health. Pathological increase in osteoclast activity causes bone loss eventually resulting in osteoporosis. Actin cytoskeleton of osteoclasts organizes into a belt of podosomes, which sustains the bone resorption apparatus and is maintained by microtubules. Better understanding of the molecular mechanisms regulating osteoclast cytoskeleton is key to understand the mechanisms of bone resorption, in particular to propose new strategies against osteoporosis. We reported recently that β-tubulin isotype TUBB6 is key for cytoskeleton organization in osteoclasts and for bone resorption. Here, using an osteoclast model CRISPR/Cas9 KO for Tubb6, we show that TUBB6 controls both microtubule and actin dynamics in osteoclasts. Osteoclasts KO for Tubb6 have reduced microtubule growth speed with longer growth life time, higher levels of acetylation and smaller EB1-caps. On the other hand, lack of TUBB6 increases podosome life time while the belt of podosomes is destabilized. Finally, we performed proteomic analyses of osteoclast microtubule-associated protein enriched fractions. This highlighted ARHGAP10 as a new microtubule-associated protein, which binding to microtubules appears to be negatively regulated by TUBB6. ARHGAP10 is a negative regulator of CDC42 activity, which participates in actin organization in osteoclasts. Our results suggest that TUBB6 plays a key role in the control of microtubule and actin cytoskeleton dynamics in osteoclasts. Moreover, by controlling ARHGAP10 association with microtubules, TUBB6 may participate in the local control CDC42 activity to ensure efficient bone resorption.

Bevacizumab-induced isolated oculomotor nerve palsy in glioblastoma multiforme

2021 ◽  
pp. 107815522110668
Author(s):  
Ezgi Değerli ◽  
Gülin Alkan ◽  
Nihan Şentürk Öztaş ◽  
Şahin Bedir ◽  
Sümeyra Derin ◽  
...  
Keyword(s):  
Side Effects ◽  
Glioblastoma Multiforme ◽  
Cranial Nerve ◽  
Nerve Palsy ◽  
Growth Factor Receptor ◽  
Recurrent Glioblastoma ◽  
Oculomotor Nerve ◽  
Oculomotor Nerve Palsy ◽  
Recurrent Glioblastoma Multiforme ◽  
Systemic Side Effects

Introduction: Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor receptor, is the standard treatment of recurrent glioblastoma multiforme. In addition to common systemic side effects of bevacizumab, there are rare cases of cranial nerve palsy. Case report: We report a case of transient oculomotor nerve palsy after systemic administration of bevacizumab. Twenty-four hours after the systemic infusion of bevacizumab, transient oculomotor nerve palsy developed in a 49-year-old male patient. In the cranial MRI, there was no malignancy-related progression. Management and outcome: Bevacizumab treatment was discontinued. Methylprednisolone was started considering that bevacizumab increased the inflammatory response. Oculomotor nerve palsy resolved in 14 days. Discussion: There are many side effects of bevacizumab whose mechanisms of action have not been fully explained. Cranial nerve involvement is rarely reported. Our case is the first reported case of bevacizumab-induced oculomotor nerve palsy.

scholarly journals Gα12/13 regulate epiboly by inhibiting E-cadherin activity and modulating the actin cytoskeleton

2009 ◽  
Vol 184 (6) ◽  
pp. 909-921 ◽  
Author(s):  
Fang Lin ◽  
Songhai Chen ◽  
Diane S. Sepich ◽  
Jennifer Ray Panizzi ◽  
Sherry G. Clendenon ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Molecular Mechanisms ◽  
Genetic Studies ◽  
Yolk Cell ◽  
Cytoskeleton Organization ◽  
Actin Cytoskeleton Organization ◽  
Cell Layers ◽  
Dependent Pathway ◽  
E Cadherin

Epiboly spreads and thins the blastoderm over the yolk cell during zebrafish gastrulation, and involves coordinated movements of several cell layers. Although recent studies have begun to elucidate the processes that underlie these epibolic movements, the cellular and molecular mechanisms involved remain to be fully defined. Here, we show that gastrulae with altered Gα12/13 signaling display delayed epibolic movement of the deep cells, abnormal movement of dorsal forerunner cells, and dissociation of cells from the blastoderm, phenocopying e-cadherin mutants. Biochemical and genetic studies indicate that Gα12/13 regulate epiboly, in part by associating with the cytoplasmic terminus of E-cadherin, and thereby inhibiting E-cadherin activity and cell adhesion. Furthermore, we demonstrate that Gα12/13 modulate epibolic movements of the enveloping layer by regulating actin cytoskeleton organization through a RhoGEF/Rho-dependent pathway. These results provide the first in vivo evidence that Gα12/13 regulate epiboly through two distinct mechanisms: limiting E-cadherin activity and modulating the organization of the actin cytoskeleton.

scholarly journals Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Gabriel L. Fiszman ◽  
María A. Jasnis
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Alternative Pathways ◽  
Downstream Signaling ◽  
Therapeutic Modalities

The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities.

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