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Additive effects of the combined expression of soluble forms of GAS1 and PTEN inhibiting glioblastoma growth

Gene Therapy volume 25, pages 439–449 (2018)Cite this article

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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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Acknowledgements

We want to thank Araceli Navarrete for technical support and Rubén Sánchez for laboratory assistance. This work was partially supported by Conacyt (México) Grant 239516 (JS).

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Authors and Affiliations

  1. Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del IPN, Av. Instituto Politécnico Nacional #2508, 07360, CDMX, Mexico

    Laura Sánchez-Hernández

  2. Departamento de Fisiología Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Av. Instituto Politécnico Nacional #2508, 07360, CDMX, Mexico

    Justino Hernández-Soto, Paula Vergara & José Segovia

  3. Departamento de Matemáticas, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco #108, 09340, CDMX, Mexico

    Rosa O. González

Authors
  1. Laura Sánchez-Hernández
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  3. Paula Vergara
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  4. Rosa O. González
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Correspondence to José Segovia.

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Sánchez-Hernández, L., Hernández-Soto, J., Vergara, P. et al. Additive effects of the combined expression of soluble forms of GAS1 and PTEN inhibiting glioblastoma growth. Gene Ther 25, 439–449 (2018). https://doi.org/10.1038/s41434-018-0020-0

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