scholarly journals Development of a NanoBRET assay to validate dual inhibitors of Sirt2-mediated lysine deacetylation and defatty-acylation that block prostate cancer cell migration

2021 ◽  
Author(s):  
Anja Vogelmann ◽  
Matthias Schiedel ◽  
Nathalie Wössner ◽  
Annika Merz ◽  
Daniel Herp ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cell ◽  
Cancer Cell Migration ◽  
Target Engagement ◽  
Cellular Functions ◽  
Anticancer Effects ◽  
Promising Target ◽  
Cellular Target ◽  
Dual Inhibitors

Sirtuin2 (Sirt2) with its NAD+-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis of many diseases, thus making Sirt2 a promising target for pharmaceutical intervention. Herein, we present new high affinity Sirt2 selective Sirtuin-Rearranging Ligands (SirReals) that inhibit both Sirt2-dependent deacetylation and defatty-acylation in vitro and in cells. We show that dual inhibition of Sirt2 results in strongly reduced levels of the oncogene c-Myc and an inhibition of cancer cell migration. Furthermore, we describe the development of a NanoBRET-based assay for Sirt2, thereby providing a method to study cellular target engagement for Sirt2 in a straightforward and accurately quantifiable manner. Applying this assay, we could confirm cellular Sirt2 binding of our new Sirt2 inhibitors and correlate their anticancer effects with their cellular target engagement.

scholarly journals Lactobacilli inhibit cervical cancer cell migration in vitro and reduce tumor burden in vivo through upregulation of E-cadherin

2017 ◽  
Vol 38 (3) ◽  
pp. 1561-1568 ◽  
Author(s):  
Xiaoxi Li ◽  
Hong Wang ◽  
Xingxing Du ◽  
Wenna Yu ◽  
Jingwen Jiang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Migration ◽  
Cancer Cell ◽  
Tumor Burden ◽  
Cervical Cancer Cell ◽  
Cancer Cell Migration ◽  
Reduce Tumor Burden ◽  
E Cadherin

scholarly journals CRMP2 as a Candidate Target to Interfere with Lung Cancer Cell Migration

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1533
Author(s):  
Xabier Morales ◽  
Rafael Peláez ◽  
Saray Garasa ◽  
Carlos Ortiz de Solórzano ◽  
Ana Rouzaut
Keyword(s):  
Cell Migration ◽  
Lung Adenocarcinoma ◽  
Cancer Cell ◽  
Adaptor Protein ◽  
Mechanistic Explanation ◽  
In Vitro Assays ◽  
Cancer Cell Migration ◽  
Cortical Actin

Collapsin response mediator protein 2 (CRMP2) is an adaptor protein that adds tubulin dimers to the growing tip of a microtubule. First described in neurons, it is now considered a ubiquitous protein that intervenes in processes such as cytoskeletal remodeling, synaptic connection and trafficking of voltage channels. Mounting evidence supports that CRMP2 plays an essential role in neuropathology and, more recently, in cancer. We have previously described a positive correlation between nuclear phosphorylation of CRMP2 and poor prognosis in lung adenocarcinoma patients. In this work, we studied whether this cytoskeleton molding protein is involved in cancer cell migration. To this aim, we evaluated CRMP2 phosphorylation and localization in the extending lamella of lung adenocarcinoma migrating cells using in vitro assays and in vivo confocal microscopy. We demonstrated that constitutive phosphorylation of CRMP2 impaired lamella formation, cell adhesion and oriented migration. In search of a mechanistic explanation of this phenomenon, we discovered that CRMP2 Ser522 phospho-mimetic mutants display unstable tubulin polymers, unable to bind EB1 plus-Tip protein and the cortical actin adaptor IQGAP1. In addition, integrin recycling is defective and invasive structures are less evident in these mutants. Significantly, mouse xenograft tumors of NSCLC expressing CRMP2 phosphorylation mimetic mutants grew significantly less than wild-type tumors. Given the recent development of small molecule inhibitors of CRMP2 phosphorylation to treat neurodegenerative diseases, our results open the door for their use in cancer treatment.

scholarly journals Wnt5a induces ROR1 to recruit cortactin to promote breast-cancer migration and metastasis

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Md Kamrul Hasan ◽  
George F. Widhopf ◽  
Suping Zhang ◽  
Sharon M. Lam ◽  
Zhouxin Shen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Surface Protein ◽  
Cancer Cell Migration ◽  
Breast Cancer Cell Migration ◽  
Promote Breast Cancer

Abstract ROR1 is a conserved oncoembryonic surface protein expressed in breast cancer. Here we report that ROR1 associates with cortactin in primary breast-cancer cells or in MCF7 transfected to express ROR1. Wnt5a also induced ROR1-dependent tyrosine phosphorylation of cortactin (Y421), which recruited ARHGEF1 to activate RhoA and promote breast-cancer-cell migration; such effects could be inhibited by cirmtuzumab, a humanized mAb specific for ROR1. Furthermore, treatment of mice bearing breast-cancer xenograft with cirmtuzumab inhibited cortactin phosphorylation in vivo and impaired metastatic development. We established that the proline at 841 of ROR1 was required for it to recruit cortactin and ARHGEF1, activate RhoA, and enhance breast-cancer-cell migration in vitro or development of metastases in vivo. Collectively, these studies demonstrate that the interaction of ROR1 with cortactin plays an important role in breast-cancer-cell migration and metastasis.

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