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Cis-Parinaric Acid Effects, Cytotoxicity, c-Jun N-terminal Protein Kinase, Forkhead Transcription Factor and Mn-SOD Differentially in Malignant and Normal Astrocytes

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Abstract

cis-Parinaric acid (c-PNA), a natural four conjugated polyunsaturated fatty acid, increases free radical production and it is preferentially cytotoxic to malignant glial cells compared to normal astrocytes in-vitro. In order to explain the increased cytotoxicity of c-PNA in malignant glial cells, we compared the effects of c-PNA on the oxidative stress-dependent signal transducing events in 36B10 cells, a malignant rat astrocytoma cell line, and in fetal rat astrocytes. Our results show that c-PNA treatment in 36B10 cells caused a persistent activation of c-Jun N-terminal protein kinase (JNK) at RNA and protein levels. Specific inhibitors of the kinase significantly reversed the cytotoxicity of c-PNA. Additionally, c-PNA caused the phosphorylated inactivation of forkhead transcription factor-3a (FKHR-L1, FOXO3a) and drastically decreased the activity of mitochondrial superoxide dismutase (Mn-SOD) that protects cells from oxidative stress. On the other hand, identical c-PNA treatments in normal astrocytes increased the dephosphorylated activation of FKHR-L1, maintained activity of Mn-SOD and failed to phosphorylate JNK. Taken together, the results imply that a selective activation of JNK and the opposite regulation of FKHR-L1 and Mn-SOD contribute to the differential cytotoxicity of c-PNA in malignant and normal glial cells.

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Abbreviations

c-PNA:

cis-Parinaric acid

SOD:

Superoxide dismutase

JNK:

c-Jun N-terminal protein kinase

FKHR:

Forkhead transcription factor

RT-PCR:

Reverse transcription-polymerase chain reaction

ELISA:

Enzyme-linked immunosorbent assay

MTT:

3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide

MAPK:

Mitogen-activated protein kinase

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Authors and Affiliations

  1. Department of Neurosurgery, University of Iowa Hospital and Clinics, Iowa, IA, 52242, USA

    Ayesha Zaheer, Shailendra K. Sahu, Timothy C. Ryken & Vincent C. Traynelis

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  1. Ayesha Zaheer
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  2. Shailendra K. Sahu
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  3. Timothy C. Ryken
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  4. Vincent C. Traynelis
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Correspondence to Shailendra K. Sahu.

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Zaheer, A., Sahu, S.K., Ryken, T.C. et al. Cis-Parinaric Acid Effects, Cytotoxicity, c-Jun N-terminal Protein Kinase, Forkhead Transcription Factor and Mn-SOD Differentially in Malignant and Normal Astrocytes. Neurochem Res 32, 115–124 (2007). https://doi.org/10.1007/s11064-006-9236-2

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