Chemo-sensitizing effects of EP4 receptor-induced inactivation of nuclear factor-κB.
Eur J Pharmacol
; 742: 81-8, 2014 Nov 05.
Article
in En
| MEDLINE
| ID: mdl-25218986
ABSTRACT
The EP4 receptor conveys growth-inhibitory effects in mature and immature B cells via NF-κB. Herein, the EP4 receptor was evaluated as a potential therapeutic target for leukemia and lymphoma, whose survival depends on the constitutive activity of NF-κB. Utilizing a pharmacological approach, we proved that the EP4 receptor induces caspase-mediated apoptosis in malignantly transformed B cells, with the most prominent effect being on Burkitt׳s lymphoma cells. Since the increased activation of NF-κB underlies multi-drug resistance phenomena, we modulated this signaling pathway via EP4 receptor triggering. Pge1-OH, a specific EP4 receptor agonist, led to decreased NF-κB activity and a consequent decrease in levels of the antiapoptotic gene Bcl-xL in Ramos cells, resulting in an elevated sensitivity of cells towards bortezomib- and doxorubicin-induced chemotherapeutic effects. Our study identifies the as yet unrecognized potential of EP4 receptor agonists as chemo-sensitizing agents in B-cell lymphoma. The specific downregulation of NF-κB-dependent pathways in B-cell malignancies opens new possibilities for treatment and current therapy optimization using specific EP4 receptor agonists.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
NF-kappa B
/
Receptors, Prostaglandin E, EP4 Subtype
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Year:
2014
Type:
Article