Combretastatin A-4 induces p53 mitochondrial-relocalisation independent-apoptosis in non-small lung cancer cells

CombretastatinA-4(CA-4)isoneofthemosteffectiveagentsusedinchemotherapy.Nevertheless,thecontributionofp53and Bim proteins in the CA-4-induced apoptosis in non-small lung cancer cells (NSCLC) remains unresolved, specifically on involving of p53 in the mitochondrial pathway activation by a transcription-independent mechanism. In this context, the p53null H1299 and wt-p53 H460 NSCLC cells, in the absence and presence of pifithrin-m (PFTm), an inhibitor of p53 mitochondrial-translocation, were treated with CA-4 and different cellular endpoints were analysed. In contrast to previous observationsinH460cells,CA-4failedintheactivationofanapoptoticresponseinH1299cells,thusindicatinganinvolvement of p53 in the cell death induced by the drug. We found that CA-4 led to p53 cellular re-localisation in H460 cells; in particular, p53 was released from the microtubular network and accumulated at mitochondria where it interacts with Bim protein and other proteins of the Bcl-2 (B-cell leukaemia-2) family, leading to cytochrome c release, alteration in the mitochondrial membrane polarisation, cell cycle arrest at the G2/M-phase, and cell death. Interestingly, the cytosolic and the mitochondrial accumulation of protein Bim was strictly dependent on p53 status. The extent of cell death was not reduced in H460 after combinedtreatmentofPFTmwithCA-4.Overall,thedatasupportamodelofCA-4-inducedapoptosisinNSCLC,forwhichthe expression of p53 protein is essential, but its mitochondrial function, linked to p53-transcription independent apoptosis pathway, is negligible.

• Autores: Méndez Callejas, Gina Marcela; Leone, Stefano; Tanzarella, Caterina; Antoccia, Antonio
• Tipo de recurso: Article of journal
• Fecha de publicación: 2014
• Institución: Universidad de Ciencias Aplicadas y Ambientales U.D.C.A
• Repositorio: Repositorio Institucional UDCA
• Idioma: eng
• OAI Identifier: oai:repository.udca.edu.co:11158/3001
• Acceso en línea: https://udca.elogim.com:2782/doi/abs/10.1002/cbin.10199
• Palabra clave: Apoptosis; Bim protein; Combretastatin A-4; Mitochondrial p53; Non-small-cell lung carcinoma; Terapéutica medicamentosa; Proteínas; Células; Neoplasmas
• Rights: openAccess
• License: Derechos Reservados - Universidad de Ciencias Aplicadas y Ambientales