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Glutathione Transferase-M2-2 Secreted from Glioblastoma Cell Protects SH-SY5Y Cells from Aminochrome Neurotoxicity

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Abstract

U373MG cells are able to take up aminochrome that induces glutathione transferase M2-2 (GSTM2) expression in a concentration-dependent manner where 100 µM aminochrome increases GSTM2 expression by 2.1-fold (P < 0.001) at 3 h. The uptake of 3H-aminochrome into U373MG cells was significantly reduced in the presence of 2 µM nomifensine (P < 0.001) 100 µM imipramine (P < 0.001) and 50 mM dopamine (P < 0.001). Interestingly, U373MG cells excrete GSTM2 into the conditioned medium and the excretion was significantly increased (2.7-fold; P < 0.001) when the cells were pretreated with 50 µM aminochrome for 3 h. The U373MG-conditioned medium containing GSTM2 protects SH-SY5Y cells incubated with 10 µM aminochrome. The significant protection provided by U373MG-conditioned medium in SH-SY5Y cells incubated with aminochrome was dependent on GSTM2 internalization into SH-SY5Y cells as evidenced by (i) uptake of 14C-GSTM2 released from U373MG cells into SH-SY5Y cells, a process inhibited by anti-GSTM2 antiserum; (ii) lack of protection of U373MG-conditioned medium in the presence of anti-GSTM2 antiserum on SH-SY5Y cells treated with aminochrome; and (iii) lack of protection of conditioned medium from U373MGsiGST6 that expresses an siRNA directed against GSTM2 on SH-SY5Y cells treated with aminochrome. In conclusion, our results demonstrated that U373MG cells protect SH-SY5Y cells against aminochrome neurotoxicity by releasing GSTM2 into the conditioned medium and subsequent internalization of GSTM2 into SH-SY5Y cells. These results suggest a new mechanism of protection of dopaminergic neurons mediated by astrocytes by releasing GSTM2 into the intersynaptic space and subsequent internalization into dopaminergic neuron in order to protect these cells against aminochrome neurotoxicity.

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Acknowledgements

Supported by FONDECYT  1100165, 1061083 (JSA) 1120337 (IP) and by Grants (to B.M.) from the Swedish Research Council and the Swedish Cancer Society.

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Authors and Affiliations

  1. Molecular and Clinical Pharmacology ICBM, Faculty of Medicine, University of Chile, Santiago, Chile

    Carlos Cuevas, Sandro Huenchuguala, Patricia Muñoz, Monica Villa, Irmgard Paris & Juan Segura-Aguilar

  2. Departamento de Ciencias Básicas, Universidad Santo Tomas, Viña del Mar, Chile

    Irmgard Paris

  3. Department of Neurochemistry Arrhenius Laboratories, Stockholm University, Stockholm, Sweden

    Bengt Mannervik

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  1. Carlos Cuevas
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  2. Sandro Huenchuguala
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  4. Monica Villa
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  6. Bengt Mannervik
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  7. Juan Segura-Aguilar
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Correspondence to Juan Segura-Aguilar.

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Cuevas, C., Huenchuguala, S., Muñoz, P. et al. Glutathione Transferase-M2-2 Secreted from Glioblastoma Cell Protects SH-SY5Y Cells from Aminochrome Neurotoxicity. Neurotox Res 27, 217–228 (2015). https://doi.org/10.1007/s12640-014-9500-1

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