Pifithrin-alpha Enhances Chemosensitivity by a p38 Mitogen-Activated Protein Kinase-Dependent Modulation of the Eukaryotic Initiation Factor 4E in Malignant Cholangiocytes

摘要

Pifithrin-alpha is the lead compound for a novel group of small molecules that are being developed for use as anticancer agents.The eukaryotic initiation factor 4E (elF-4E) is overex-pressed in many cancers,it can mediate sensitivity to therapy,and it may be regulated by p53.We examined the utility of pifithrin-alpha as an adjunct to therapy for the treatment of human cholangiocarcinoma,a tumor that is highly refractory to therapy,and we assessed the involvement of p53-dependent elF-4E regulation in cellular responses to pifithrin-alpha.The expression of elF-4E was increased in human cholangiocarcino-mas compared with normal liver.Modulation of elF-4E expression by RNA interference enhanced the efficacy of gemcitabine in KMCH cholangiocarcinoma cells.Preincubation of KMCH cells with pifithrin-alpha enhanced gemcitabine-induced cytotoxicity in an elF-4E-dependent manner.Furthermore,pifithrin-alpha increased elF-4E phosphorylation at serine 209 via activation of p38 mitogen-activated protein kinase (MAPK).Pifithrin-alpha was shown to activate aryl hydrocarbon receptor (AhR) signaling and p38 MAPK activation.Sequencing analysis indicated the presence of a functionally inactivating p53 mutation in KMCH cells,and small interfering RNA to p53 did not modulate che-mosensitization by pifithrin-alpha.Pifithrin-alpha enhanced chemosen-sitivity by a mechanism independent of p53 and involving AhR and p38 MAPK deregulation of elF-4E phosphorylation.Thus,pifithrin-alpha may prove useful for enhancing chemosensitivity in tumors with mutated p53.Moreover,modulation of elF-4E is an attractive therapeutic target for intervention in cancer treatment.