Cis-parinaric acid effects, cytotoxicity, c-Jun N-terminal protein kinase, forkhead transcription factor and Mn-SOD differentially in malignant and normal astrocytes.
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.
Zaheer
Ayesha
A
Department of Neurosurgery, University of Iowa Hospital and Clinics, Iowa, IA 52242, USA.
Sahu
Shailendra K
SK
Ryken
Timothy C
TC
Traynelis
Vincent C
VC
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001254:Astrocytoma / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000633:toxicity*; D005419:Flavonoids / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D051381:Rats; D011916:Rats, Inbred F344; D013482:Superoxide Dismutase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects
C499515:FOXO3 protein, rat; D005231:Fatty Acids, Unsaturated; D005419:Flavonoids; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005609:Free Radicals; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D003474:Curcumin; C013641:parinaric acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one