title: Lupulone triggers p38 MAPK-controlled activation of p53 and of the TRAIL receptor apoptotic pathway in human colon cancer-derived metastatic cells.
abstract: We previously reported that the chemopreventive agent lupulone induces apoptosis through activation of the extrinsic pathway via TRAIL DR4/DR5 death receptors overcoming SW620 cell resistance to TRAIL. However, the underlying molecular mechanisms remain unknown. Since the mitogen-activated protein kinases (MAPKs), Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 control fundamental cellular processes such as apoptosis, we determined the role of these MAPKs in lupulone-triggered apoptosis. We analyzed the effects of JNK, ERK and p38 MAPK inhibitors on lupulone-induced apoptosis by flow cytometry using specific antibodies and real-time RT-PCR. Our data showed that among the MAPKs, only p38 played a major role in lupulone-triggered apoptosis. In contrast to JNK and ERK inhibition, the specific inactivation of p38 inhibited the lupulone-triggered up-regulation of p53 and TRAIL-death receptor DR4/DR5 expression, and prevented DNA fragmentation. Lupulone treatment enhanced the expression of the anti-apoptotic Mcl-1 protein by 60% favoring the preservation of mitochondrial integrity. The inactivation of p38 initiated a 50% reduction in Mcl-1, Bcl-2 and Bax expression without changing the Mcl-1/Bax ratio suggesting that p38 was not involved in the protective effect of lupulone on mitochondria. Our data support the view that the lupulone-triggered enhanced expression of p38 plays a major role in the activation of p53 and of the TRAIL-death receptor apoptotic pathway in SW620 human colon cancer-derived metastatic cells.
authors.affiliation: Unit of Physiopathology and Translational Research EA 4438, University of Strasbourg, Faculty of Medicine, Strasbourg, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Lamy
authors.forename: Souad
authors.initials: S
authors.lastname: Bousserouel
authors.forename: Francine
authors.initials: F
authors.lastname: Gossé
authors.forename: Carole
authors.initials: C
authors.lastname: Minker
authors.forename: Annelise
authors.initials: A
authors.lastname: Lobstein
authors.forename: Francis
authors.initials: F
authors.lastname: Raul
mesh_terms: D017209:Apoptosis; D016923:Cell Death; D003110:Colonic Neoplasms / Q000378:metabolism*; D053938:DNA Fragmentation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D009362:Neoplasm Metastasis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C495901:TP53 protein, human; D013729:Terpenes; D016159:Tumor Suppressor Protein p53; C008299:lupulon; D048051:p38 Mitogen-Activated Protein Kinases