Dataset Information

Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines.

ABSTRACT: The post?translational modification of proteins by ubiquitinating enzymes plays a central role in a number of cellular functions, such as cell proteolysis, DNA repair, and cell signaling and communication. Deubiquitinating enzymes (DUBs) disassemble ubiquitin chains and remove ubiquitin moieties from proteins. Targeting DUBs in cancer models has revealed an important role for these enzymes in tumorigenesis, and they therefore have emerged as attractive therapeutic targets. In the present study, the effects of three DUB inhibitors, PR?619, RA?9 and LDN?91946, on a non?small cell lung cancer cell line (A549) and a mesothelioma cell line (H2373) were investigated. PR?619 significantly inhibited cell adhesion and the proliferation of both cell lines. RA?9 exerted an inhibitory effect on the adhesion and proliferation of H2373 cells, whereas it had no effect on A549 cells. Notably, however, while PR?619 attenuated the proliferation of both cell lines, it exerted an opposite effect on cell motility; in the case of A549 cells, there was a significant increase in cell motility, while for the H2373 cells, there was a significant decrease. Furthermore, protein phosphorylation kinetic analyses revealed that the effects were cell line?specific. In H2373 cells, the phosphorylation of only one peptide corresponding to the P85A protein was significantly affected, and while LDN?91946 treatment increased phosphorylation, treatment with RA?9 or PR?619 decreased its phosphorylation compared to the DMSO control. By contrast, in the case of A549 cells, the phosphorylation of 21 peptides was significantly affected by the same compounds. In light of the potential for the negative side?effects of DUB inhibition, such as increased cancer cell motility, the data presented herein underscore the dire need for the development of specific DUB inhibitors and to elucidate the individual role of DUB family members in cancer biology before they can be specifically pharmacologically targeted.

SUBMITTER: Mirzapoiazova T

PROVIDER: S-EPMC7252467 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines.

Mirzapoiazova Tamara T Pozhitkov Alexander A Nam Arin A Mambetsariev Isa I Nelson Michael S MS Tan Yi-Hung Carol YC Zhang Keqiang K Raz Dan D Singhal Sharad S Nasser Mohd W MW Kulkarni Prakash P Batra Surinder K SK Sattler Martin M Salgia Ravi R

International journal of oncology 20200401 1

The post‑translational modification of proteins by ubiquitinating enzymes plays a central role in a number of cellular functions, such as cell proteolysis, DNA repair, and cell signaling and communication. Deubiquitinating enzymes (DUBs) disassemble ubiquitin chains and remove ubiquitin moieties from proteins. Targeting DUBs in cancer models has revealed an important role for these enzymes in tumorigenesis, and they therefore have emerged as attractive therapeutic targets. In the present study, ...[more]

PMID: 32236606

Similar Datasets

Project description:Despite being subjected to high dose chemo and radiotherapy, glioblastoma (GBM) patients still encounter almost inevitable relapse due to the capability of tumor cells to disseminate and invade normal brain tissues. Moreover, the presence of a Cancer Stem Cell (CSC) subpopulation, already demonstrated to better resist and evade treatments, further frustrate potential therapeutic approaches. In this context, we previously demonstrated that GBM is characterized by a tightly regulated balance between the β-catenin cofactors TCF1 and TCF4, with high levels of TCF4 responsible for sustaining CSC in these tumors, thus supporting their aggressive features. Since Histone Deacetylase Inhibitors (HDI) have been reported to strongly reduce TCF4 levels in colon cancer cells, we hypothesized they could exert a similar therapeutic action also in GBM. Here, we treated primary GBM cultures with Trichostatin-A and Vorinostat, demonstrating their ability to strongly suppress the Wnt dependent pathways, thus promoting CSC differentiation, and concomitantly impairing GBM cell viability and proliferation. More interestingly, analysis of their molecular effects suggested a prominent HDI action against GBM cell motility/migration, that we demonstrated to be dependent on the inhibition of the RhoA-GTPase and interferon intracellular cascades. Our results suggest HDI as potential therapeutic agents in GBM through their action on multiple cancer hallmarks. Glioblastoma (GBM) is considered the deadliest brain tumor, with patients displaying a high incidence of relapse and a 3-year survival of only 3-5%. For these reasons, investigation of the molecular basis of the disease could provide novel targets for therapy and improve patient prognosis. Based on our previous data demonstrating that high levels of the transcription factor TCF4 (TCF7L2) sustain the aggressiveness and the stem cell features of these tumors, in this study we tested the ability of the histone deacetylase inhibitors (HDI) Trichostatin-A and Vorinostat to suppress TCF4 levels. We demonstrated that HDI treatment impairs proliferation and viability of GBM cells. Moreover, molecular analysis of HDI effects disclosed their ability to counteract tumor cell motility by affecting the RhoA-GTPase and the interferon pathways, supporting their further characterization as potential anti-GBM agents

Dataset Information

Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines.

Publications

Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets