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: Virginie Lamy, Souad Bousserouel, Francine Gossé, Carole Minker, Annelise Lobstein, Francis Raul
• Journal: Oncology reports (Oncol Rep) Vol. 26 Issue 1 Pg. 109-14 (Jul 2011) ISSN: 1791-2431 [Electronic] Greece
• PMID: 21519792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10A protein, human
• TNFSF10 protein, human
• TP53 protein, human
• Terpenes
• Tumor Suppressor Protein p53
• lupulon
• p38 Mitogen-Activated Protein Kinases

Topics

• Apoptosis
• Cell Death
• Colonic Neoplasms (metabolism)
• DNA Fragmentation
• Gene Expression Regulation, Neoplastic
• Humans
• Models, Biological
• Neoplasm Metastasis
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Terpenes (pharmacology)
• Time Factors
• Tumor Suppressor Protein p53 (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)