The necrotic signal induced by mycophenolic acid overcomes apoptosis-resistance in tumor cells

• Published in: PloS one 2009-05, Vol.4 (5), p.e5493-e5493
• Main Authors: Guidicelli, Gwendaline, Chaigne-Delalande, Benjamin, Dilhuydy, Marie-Sarah, Pinson, Benoît, Mahfouf, Walid, Pasquet, Jean-Max, Mahon, François-Xavier, Pourquier, Philippe, Moreau, Jean-François, Legembre, Patrick
• Format: Article
• Language: English
• Subjects: Abl protein; Acid resistance; Acids; Antiviral agents; Apoptosis; Apoptosis - drug effects; B cells; BCR protein; BCR-ABL protein; Biosynthesis; Blotting, Western; Cancer therapies; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cdc42 protein; Cell Biology/Cell Signaling; Cell Biology/Cellular Death and Stress Responses; Cell death; Cell Line; Cell Line, Tumor; Chronic lymphocytic leukemia; Cloning; Cytoskeleton; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Ectopic expression; Enzymes; Fusion protein; Gene expression; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Growth models; Guanosine; Guanosine diphosphate; Guanosine Diphosphate - metabolism; Guanosine triphosphatases; Guanosine triphosphate; Guanosine Triphosphate - metabolism; Heat shock proteins; Hsp70 protein; Humans; Immunosuppressive agents; IMP Dehydrogenase - antagonists & inhibitors; IMP Dehydrogenase - metabolism; Inhibition; Inosine monophosphate; Jurkat Cells; K562 Cells; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - blood; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Life Sciences; Ligands; Lymphatic leukemia; Lymphocytes; Lymphocytes - metabolism; Lymphocytes - pathology; Lymphocytes - ultrastructure; Microscopy, Electron; Multiple myeloma; Mutation; Mycophenolic acid; Mycophenolic Acid - pharmacology; Necrosis - chemically induced; Oncology/Hematological Malignancies; Phosphates; Physiological aspects; Plasmids; Ribavirin; RNA, Small Interfering - genetics; Signal processing; Signal transduction; Signal Transduction - drug effects; Transfection; Transplants & implants; Tumor cells; Tumor Cells, Cultured; Tumor necrosis factor-TNF; Tumorigenesis; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005493

The amount of inosine monophosphate dehydrogenase (IMPDH), a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP), is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA) are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42. Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA-mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL-overexpressing cells). All tested cells remained sensitive to MPA-mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers. These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells.