Article ; Online: Additive effects of the combined expression of soluble forms of GAS1 and PTEN inhibiting glioblastoma growth.
2018 Volume 25, Issue 6, Page(s) 439–449
Abstract: The overexpression of GAS1 (Growth Arrest Specific 1) in glioma cells induces cell cycle arrest and apoptosis. We previously demonstrated that the apoptotic process set off by GAS1 is caused by its capacity to inhibit the Glial cell-derived neurotrophic ... ...
| Abstract | The overexpression of GAS1 (Growth Arrest Specific 1) in glioma cells induces cell cycle arrest and apoptosis. We previously demonstrated that the apoptotic process set off by GAS1 is caused by its capacity to inhibit the Glial cell-derived neurotrophic factor (GDNF)-mediated intracellular survival signaling pathway. Whereas on the other hand, PTEN is a tumor suppressor, inactive in many tumors, and both GAS1 and PTEN inhibit the PI3K/AKT pathway. Therefore, it is relevant to investigate the potential additive effect of the overexpression of GAS1 and PTEN on tumor growth. In particular, we employed secreted forms of both GAS1 (tGAS1) and PTEN (PTEN-LONG, or PTEN-L) and tested their combined effect on glioma cells. We observed that the co-expression of both the proteins inhibited the growth of U-87 MG human glioblastoma cells more effectively than when independently expressed, and decreased the activity of both AKT and ERK1/2. Interestingly, the combination of the soluble forms was always the most effective treatment. To improve the transfer of tGAS1 and PTEN-L, we employed a lentiviral vector with a p2A peptide-enabled dual expression system that allowed the generation of the two proteins using a single promoter (CMV), in equimolar amounts. The viral vector reduced the growth of U-87 MG cells in vitro and had a striking effect in inhibiting their proliferation after inoculating it into the immunosuppressed mice. The present results support a potential adjuvant role for the combined use of tGAS1 and PTEN-L in the treatment of glioblastoma. |
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| MeSH term(s) | Animals ; Apoptosis/drug effects ; Apoptosis/genetics ; Cell Cycle Proteins/administration & dosage ; Cell Cycle Proteins/genetics ; Cell Proliferation/drug effects ; GPI-Linked Proteins/administration & dosage ; GPI-Linked Proteins/genetics ; Gene Expression Regulation, Neoplastic ; Genetic Vectors/administration & dosage ; Genetic Vectors/immunology ; Glial Cell Line-Derived Neurotrophic Factor/genetics ; Glioblastoma/genetics ; Glioblastoma/immunology ; Glioblastoma/pathology ; Glioblastoma/therapy ; Humans ; Lentivirus/genetics ; Mice ; PTEN Phosphohydrolase/administration & dosage ; PTEN Phosphohydrolase/genetics ; Xenograft Model Antitumor Assays |
| Chemical Substances | Cell Cycle Proteins ; GAS1 protein, human ; GPI-Linked Proteins ; Glial Cell Line-Derived Neurotrophic Factor ; PTEN Phosphohydrolase (EC 3.1.3.67) |
| Language | English |
| Publishing date | 2018-06-25 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1191036-7 |
| ISSN | 1476-5462 ; 0969-7128 |
| ISSN (online) | 1476-5462 |
| ISSN | 0969-7128 |
| DOI | 10.1038/s41434-018-0020-0 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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