Susceptibility of cholangiocarcinoma cells to parthenolide-induced apoptosis.
Cholangiocarcinomas are intrahepatic bile duct carcinomas that are known to have a poor prognosis. Sesquiterpene lactone parthenolide, which is the principal active component in medicinal plants, has been used to treat tumors. Parthenolide effectively induced apoptosis in all four cholangiocarcinoma cell lines in a dose-dependent manner. However, the sarcomatous SCK cells were more sensitive to parthenolide than the other adenomatous cholangiocarcinoma cells. Therefore, this study investigated whether or not the expression of p53, the Fas/Fas ligand (FasL), Bcl-2/Bcl-X(L) determines the enhanced drug susceptibility of SCK cells. The results showed that Bcl-2 family molecules, such as Bid, Bak, and Bax, are involved in the parthenolide-induced apoptosis and that the defective expression of Bcl-X(L) might contribute to the higher parthenolide sensitivity in the SCK cells than in the other adenomatous cholangiocarcinoma cells. SCK cells, which stably express Bcl-X(L), were resistant to parthenolide, whereas Bcl-X(L)-positive Choi-CK cells transfected with the antisense Bcl-X(L) showed a higher parthenolide sensitivity than the vector control cells. Molecular dissection revealed that Bcl-X(L) inhibited the translocation of Bax to the mitochondria, decreased the generation of intracellular reactive oxygen species, reduced the mitochondrial transmembrane potential (deltapsi(m)), decreased the release of cytochrome c, decreased the cleavage of poly(ADP-ribose) polymerase, and eventually inhibited apoptotic cell death. These results suggest that parthenolide effectively induces oxidative stress-mediated apoptosis, and that the susceptibility to parthenolide in cholangiocarcinoma cells might be modulated by Bcl-X(L) expression in association with Bax translocation to the mitochondria.
Kim
Jong-Hyun
JH
Division of GI and Hepatology, Department of Internal Medicine, Institute for Molecular Biology and Genetics, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
Liu
Lan
L
Lee
Seung-Ok
SO
Kim
Yong-Tae
YT
You
Kyung-Ran
KR
Kim
Dae-Ghon
DG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor / Q000096:biosynthesis
D000970:Antineoplastic Agents; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor; C002669:parthenolide; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases