Paradoxical role of 3-methyladenine in pyocyanin-induced toxicity in 1321N1 astrocytoma and SH-SY5Y neuroblastoma cells

Amelia J. McFarland, Gary D. Grant, Anthony V. Perkins, Cameron Flegg, Andrew K. Davey, Tristan J. Allsopp, Gillian Renshaw, Justin Kavanagh, Catherine M. McDermott, Shailendra Anoopkumar-Dukie*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

The role of autophagy in pyocyanin (PCN)-induced toxicity in the central nervous system (CNS) remains unclear, with only evidence from our group identifying it as a mechanism underlying toxicity in 1321N1 astrocytoma cells. Therefore, the aim of this study was to further examine the role of autophagy in PCN-induced toxicity in the CNS. To achieve this, we exposed 1321N1 astrocytoma and SH-SY5Y neuroblastoma cells to PCN (0-100 μmol/L) and tested the contribution of autophagy by measuring the impact of the autophagy inhibitor 3-methyladenine (3-MA) using a series of biochemical and molecular markers. Pretreatment of 1321N1 astrocytoma cells with 3-MA (5 mmol/L) decreased the PCN-induced acidic vesicular organelle and autophagosome formation as measured using acridine orange and green fluorescent protein-LC3 -LC3 fluorescence, respectively. Furthermore, 3-MA (5 mmol/L) significantly protected 1321N1 astrocytoma cells against PCN-induced toxicity. In contrast pretreatment with 3-MA (5 mmol/L) increased PCN-induced toxicity in SH-SY5Y neuroblastoma cells. Given the influence of autophagy in inflammatory responses, we investigated whether the observed effects in this study involved inflammatory mediators. The PCN (100 μmol/L) significantly increased the production of interleukin-8 (IL-8), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) in both cell lines. Consistent with its paradoxical role in modulating PCN-induced toxicity, 3-MA (5 mmol/L) significantly reduced the PCN-induced production of IL-8, PGE2, and LTB4 in 1321N1 astrocytoma cells but augmented their production in SH-SY5Y neuroblastoma cells. In conclusion, we show here for the first time the paradoxical role of autophagy in mediating PCN-induced toxicity in 1321N1 astrocytoma and SH-SY5Y neuroblastoma cells and provide novel evidence that these actions may be mediated by effects on IL-8, PGE2, and LTB4 production.

Original languageEnglish
Pages (from-to)209-218
Number of pages10
JournalInternational Journal of Toxicology
Volume32
Issue number3
DOIs
Publication statusPublished - May 2013

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    McFarland, A. J., Grant, G. D., Perkins, A. V., Flegg, C., Davey, A. K., Allsopp, T. J., Renshaw, G., Kavanagh, J., McDermott, C. M., & Anoopkumar-Dukie, S. (2013). Paradoxical role of 3-methyladenine in pyocyanin-induced toxicity in 1321N1 astrocytoma and SH-SY5Y neuroblastoma cells. International Journal of Toxicology, 32(3), 209-218. https://doi.org/10.1177/1091581813482146