Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells.
10.3858/emm.2010.42.11.082
- Author:
Bo Ra YUN
1
;
Mi Jin LEE
;
Jong Hyun KIM
;
In Hee KIM
;
Goung Ran YU
;
Dae Ghon KIM
Author Information
1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju 561-712, Korea. daeghon@chonbuk.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
cholangiocarcinoma;
drug therapy;
heme oxygenase-1;
parthenolide;
protein kinase C-alpha
- MeSH:
Active Transport, Cell Nucleus/drug effects;
Antineoplastic Agents/chemistry/*pharmacology;
Apoptosis/drug effects/genetics;
Cell Line, Tumor;
Cell Nucleus/*metabolism;
Cholangiocarcinoma/drug therapy/*metabolism/pathology;
Drug Resistance, Neoplasm/drug effects/genetics;
Enzyme Activation;
Enzyme Inhibitors/pharmacology;
Heme Oxygenase-1/genetics/*metabolism;
Humans;
Lactones/chemistry;
NF-E2-Related Factor 2/genetics/*metabolism;
Protein Kinase C-alpha/antagonists & inhibitors;
RNA, Small Interfering/genetics;
Sesquiterpenes/chemistry/*pharmacology;
Signal Transduction/drug effects
- From:Experimental & Molecular Medicine
2010;42(11):787-797
- CountryRepublic of Korea
- Language:English
-
Abstract:
Cholangiocarcinoma (CC) is a chemoresistant intrahepatic bile duct carcinoma with a poor prognosis. The aims of this study were to identify molecular pathways that enhance sesquiterpene lactone parthenolide (PTL)-induced anticancer effects on CC cells. The effects of PTL on apoptosis and hemoxygenase-1 (HO-1) induction were examined in CC cell lines. The enhancement of PTL-mediated apoptosis by modulation of HO-1 expression and the mechanisms involved were also examined in an in vitro cell system. Low PTL concentrations (5 to 10 micrometer) led to Nrf2-dependent HO-1 induction, which attenuated the apoptogenic effect of PTL in Choi-CK and SCK cells. PTL-mediated apoptosis was enhanced by the protein kinase C-alpha inhibitor Ro317549 (Ro) through inhibition of expression and nuclear translocation of Nrf2, resulting in blockage of HO-1 expression. Finally, HO-1 silencing resulted in enhancement of apoptotic cell death in CC cells. The combination of PTL and Ro efficiently improved tumor growth inhibition compared to treatment with either agent alone in an in vivo subcutaneous tumor model. In conclusion, the modulation of HO-1 expression substantially improved the anticancer effect of PTL. The combination of PTL and Ro could prove to be a valuable chemotherapeutic strategy for CC.
