RedOx status, proteasome and APEH: insights into anticancer mechanisms of t10,c12-conjugated linoleic acid isomer on A375 melanoma cells.

Abstract

This study describes the investigation of the efficiency of conjugated linoleic acid (CLA) isomers in reducing cancer cells viability exploring the role of the oxidative stress and acylpeptide hydrolase (APEH)/proteasome mediated pathways on pro-apoptotic activity of the isomer trans10,cis12 (t10,c12)-CLA. The basal activity/expression levels of APEH and proteasome (β-5 subunit) were preliminarily measured in eight cancer cell lines and the functional relationship between these enzymes was clearly demonstrated through their strong positive correlation. t10,c12-CLA efficiently inhibited the activity of APEH and proteasome isoforms in cell-free assays and the negative correlation between cell viability and caspase 3 activity confirmed the pro-apoptotic role of this isomer. Finally, modulatory effects of t10,c12-CLA on cellular redox status (intracellular glutathione, mRNA levels of antioxidant/detoxifying enzymes activated through NF-E2-related factor 2, Nrf2, pathway) and on APEH/β-5 activity/expression levels, were investigated in A375 melanoma cells. Dose- and time-dependent variations of the considered parameters were established and the resulting pro-apoptotic effects were shown to be associated with an alteration of the redox status and a down-regulation of APEH/proteasome pathway. Therefore, our results support the idea that these events are involved in ROS-dependent apoptosis of t10,c12-CLA-treated A375 cells. The combined inhibition, triggered by t10,c12-CLA, via the modulation of APEH/proteasome and Nrf2 pathway for treating melanoma, is suggested as a subject for further in vivo studies.

• Authors: Paolo Bergamo, Ennio Cocca, Rosanna Palumbo, Marta Gogliettino, Mose Rossi, Gianna Palmieri
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e80900 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24260504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Linoleic Acids, Conjugated
• NF-E2 Transcription Factor, p45 Subunit
• NFE2 protein, human
• Reactive Oxygen Species
• trans-10,cis-12-conjugated linoleic acid
• Peptide Hydrolases
• acylaminoacyl-peptidase
• Caspase 3
• PSMB5 protein, human
• Proteasome Endopeptidase Complex

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (genetics, metabolism)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic
• Humans
• Kinetics
• Linoleic Acids, Conjugated (pharmacology)
• NF-E2 Transcription Factor, p45 Subunit (agonists, genetics, metabolism)
• Oxidation-Reduction
• Oxidative Stress
• Peptide Hydrolases (genetics, metabolism)
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction