Role of PKC-delta activity in glutathione-depleted neuroblastoma cells.
Protein kinases C (PKCs) are a family of isoenzymes sensitive to oxidative modifications and involved in the transduction signal pathways that regulate cell growth. As such, they can act as cellular sensors able to intercept intracellular redox changes and promote the primary adaptive cell response. In this study, we have demonstrated that PKC isoforms are specifically influenced by the amount of intracellular glutathione (GSH). The greatest GSH depletion is associated with a maximal reactive oxygen species (ROS) production and accompanied by an increase in the activity of the delta isoform and a concomitant inactivation of alpha. ROS generation induced early morphological changes in GSH-depleted neuroblastoma cells characterized, at the intracellular level, by the modulation of PKC-delta activity that was involved in the pathway leading to apoptosis. When cells were pretreated with rottlerin, their survival was improved by the ability of this compound to inhibit the activity of PKC-delta and to counteract ROS production. These results define a novel role of PKC-delta in the cell signaling pathway triggered by GSH loss normally associated with many neurodegenerative diseases and clinically employed in the treatment of neuroblastoma.
Domenicotti
Cinzia
C
Department of Experimental Medicine, Section of General Pathology, University of Genoa, Genoa, Italy. cdmeni@medicina.unige.it
Marengo
Barbara
B
Verzola
Daniela
D
Garibotto
Giacomo
G
Traverso
Nicola
N
Patriarca
Stefania
S
Maloberti
Giuseppe
G
Cottalasso
Damiano
D
Poli
Giuseppe
G
Passalacqua
Mario
M
Melloni
Edon
E
Pronzato
Maria Adelaide
MA
Marinari
Umberto Maria
UM
D000098:Acetophenones / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001205:Ascorbic Acid / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D008315:Malondialdehyde; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051745:Protein Kinase C-delta; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure
D000098:Acetophenones; D000975:Antioxidants; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D019328:Buthionine Sulfoximine; C085746:rottlerin; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005978:Glutathione; D001205:Ascorbic Acid