Inhibition of Lon protease by triterpenoids alters mitochondria and is associated to cell death in human cancer cells

Mitochondrial Lon protease (Lon) regulates several mitochondrial functions, and is inhibited by the anticancer molecule triterpenoid 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), or by its C-28 methyl ester derivative (CDDO-Me). To analyze the mechanism of action of triterpenoids, we in...

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Bibliographic Details
Published in:	Oncotarget 2015-09, Vol.6 (28), p.25466-25483
Main Authors:	Gibellini, Lara, Pinti, Marcello, Bartolomeo, Regina, De Biasi, Sara, Cormio, Antonella, Musicco, Clara, Carnevale, Gianluca, Pecorini, Simone, Nasi, Milena, De Pol, Anto, Cossarizza, Andrea
Format:	Article
Language:	eng
Subjects:	Aconitate Hydratase - metabolism Antineoplastic Agents - pharmacology Apoptosis - drug effects ATP-Dependent Proteases - antagonists & inhibitors ATP-Dependent Proteases - genetics ATP-Dependent Proteases - metabolism Cell Death - drug effects Cell Proliferation - drug effects DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug Hep G2 Cells Humans Hydrogen Peroxide - metabolism MCF-7 Cells Membrane Potential, Mitochondrial - drug effects Mitochondria - drug effects Mitochondria - enzymology Mitochondria - pathology Mitochondrial Dynamics - drug effects Mitochondrial Proteins - antagonists & inhibitors Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Neoplasms - drug therapy Neoplasms - enzymology Neoplasms - genetics Neoplasms - pathology Oleanolic Acid - analogs & derivatives Oleanolic Acid - pharmacology Oxidative Stress - drug effects Protease Inhibitors - pharmacology Protein Carbonylation - drug effects Research Paper Signal Transduction - drug effects Superoxides - metabolism Time Factors Transcription Factors - metabolism Transfection
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Summary:	Mitochondrial Lon protease (Lon) regulates several mitochondrial functions, and is inhibited by the anticancer molecule triterpenoid 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), or by its C-28 methyl ester derivative (CDDO-Me). To analyze the mechanism of action of triterpenoids, we investigated intramitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, mitochondrial mass, mitochondrial dynamics and morphology, and Lon proteolytic activity in RKO human colon cancer cells, in HepG2 hepatocarcinoma cells and in MCF7 breast carcinoma cells. We found that CDDO and CDDO-Me are potent stressors for mitochondria in cancer cells, rather than normal non-transformed cells. In particular, they: i) cause depolarization; ii) increase mitochondrial ROS, iii) alter mitochondrial morphology and proteins involved in mitochondrial dynamics; iv) affect the levels of Lon and those of aconitase and human transcription factor A, which are targets of Lon activity; v) increase level of protein carbonyls in mitochondria; vi) lead to intrinsic apoptosis. The overexpression of Lon can rescue cells from cell death, providing an additional evidence on the role of Lon in conditions of excessive stress load.
ISSN:	1949-2553 1949-2553