TY - JOUR
T1 - Pifithrin-α enhances chemosensitivity by a p38 mitogen-activated protein kinase-dependent modulation of the eukaryotic initiation factor 4E in malignant cholangiocytes
AU - Wehbe, Hania
AU - Henson, Roger
AU - Lang, Molly
AU - Meng, Fanyin
AU - Patel, Tushar
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006
Y1 - 2006
N2 - Pifithrin-α 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 (eIF-4E) is overexpressed in many cancers, it can mediate sensitivity to therapy, and it may be regulated by p53. We examined the utility of pifithrin-α 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 eIF-4E regulation in cellular responses to pifithrin-α. The expression of eIF-4E was increased in human cholangiocarcinomas compared with normal liver. Modulation of eIF-4E expression by RNA interference enhanced the efficacy of gemcitabine in KMCH cholangiocarcinoma cells. Preincubation of KMCH cells with pifithrin-α enhanced gemcitabine-induced cytotoxicity in an eIF-4E-dependent manner. Furthermore, pifithrin-α increased eIF-4E phosphorylation at serine 209 via activation of p38 mitogen-activated protein kinase (MAPK). Pifithrin-α 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 chemosensitization by pifithrin-α. Pifithrin-α enhanced chemosensitivity by a mechanism independent of p53 and involving AhR and p38 MAPK deregulation of eIF-4E phosphorylation. Thus, pifithrin-α may prove useful for enhancing chemosensitivity in tumors with mutated p53. Moreover, modulation of eIF-4E is an attractive therapeutic target for intervention in cancer treatment.
AB - Pifithrin-α 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 (eIF-4E) is overexpressed in many cancers, it can mediate sensitivity to therapy, and it may be regulated by p53. We examined the utility of pifithrin-α 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 eIF-4E regulation in cellular responses to pifithrin-α. The expression of eIF-4E was increased in human cholangiocarcinomas compared with normal liver. Modulation of eIF-4E expression by RNA interference enhanced the efficacy of gemcitabine in KMCH cholangiocarcinoma cells. Preincubation of KMCH cells with pifithrin-α enhanced gemcitabine-induced cytotoxicity in an eIF-4E-dependent manner. Furthermore, pifithrin-α increased eIF-4E phosphorylation at serine 209 via activation of p38 mitogen-activated protein kinase (MAPK). Pifithrin-α 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 chemosensitization by pifithrin-α. Pifithrin-α enhanced chemosensitivity by a mechanism independent of p53 and involving AhR and p38 MAPK deregulation of eIF-4E phosphorylation. Thus, pifithrin-α may prove useful for enhancing chemosensitivity in tumors with mutated p53. Moreover, modulation of eIF-4E is an attractive therapeutic target for intervention in cancer treatment.
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U2 - 10.1124/jpet.106.109835
DO - 10.1124/jpet.106.109835
M3 - Article
C2 - 16982703
AN - SCOPUS:33751173877
SN - 0022-3565
VL - 319
SP - 1153
EP - 1161
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -