title: RITA can induce cell death in p53-defective cells independently of p53 function via activation of JNK/SAPK and p38.
abstract: Significant advances have been made in the development of small molecules blocking the p53/MDM2 interaction. The Mdm2 inhibitor Nutlin-3 is restricted to tumors carrying wtp53. In contrast, RITA, a compound that binds p53, has recently been shown also to restore transcriptional functions of mtp53. As more than 50% of solid tumors carry p53 mutations, RITA promises to be a more effective therapeutic strategy than Nutlin-3. We investigated effects of RITA on apoptosis, cell cycle and induction of 45 p53 target genes in a panel of 14 cell lines from different tumor entities with different p53 status as well as primary lymphocytes and fibroblasts. Nine cell strains expressed wtp53, four harbored mtp53, and three were characterized by the loss of p53 protein. A significant induction of cell death upon RITA was observed in 7 of 16 cell lines. The nonmalignant cells in our panel were substantially less sensitive. We found that in contrast to Nultin-3, RITA is capable to induce cell death not only in tumor cells harboring wtp53 and mtp53 but also in p53-null cells. Importantly, whereas p53 has a central role for RITA-mediated effects in wtp53 cells, neither p53 nor p63 or p73 were essential for the RITA response in mtp53 or p53-null cells in our panel demonstrating that besides the known p53-dependent action of RITA in wtp53 cells, RITA can induce cell death also independently of p53 in cells harboring defective p53. We identified an important role of both p38 and JNK/SAPK for sensitivity to RITA in these cells leading to a typical caspase- and BAX/BAK-dependent mitochondrial apoptosis. In conclusion, our data demonstrate that RITA can induce apoptosis through p38 and JNK/SAPK not only in tumor cells harboring wtp53 and mtp53 but also in p53-null cells, making RITA an interesting tumor-selective drug.
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Auerbachstrasse 112, Stuttgart, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Weilbacher
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Auerbachstrasse 112, Stuttgart, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gutekunst
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Oren
authors.affiliation: Second Department of Internal Medicine, Robert-Bosch-Hospital, Auerbachstrasse 110, Stuttgart, Germany.
authors.forename: W E
authors.initials: WE
authors.lastname: Aulitzky
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Auerbachstrasse 112, Stuttgart, Germany.
authors.forename: H
authors.initials: H
authors.lastname: van der Kuip
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; C118989:NSC 652287; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020169:Caspases