An exogenous cdk inhibitor, butyrolactone-I, induces apoptosis with increased Bax/Bcl-2 ratio in p53-mutated pancreatic cancer cells.
We investigated the effects of an exogenous cdk inhibitor, butyrolactone-I, on cell growth inhibition, apoptosis induction, and the regulation of apoptosis in pancreatic cancer cells with mutated p53. Cell growth was dose-dependently inhibited by Butyrolactone-I in PANC-1 and AsPC-1 cells. Phosphorylation of pRb and Cyclin A expression were significantly inhibited in Butyrolactone-I-treated cells. Apoptotic cell death was detected by both Hoechst staining and TUNEL assay. In butyrolactone-I-treated PANC-1 cells, expression of p53 protein was unchanged, but Bax expression was slightly upregulated and Bcl-2 expression was predominantly down-regulated. Bax/Bcl-2 ratio reached 9.6-fold increase compared to the control at the maximum. The time course of changes in Bax/Bcl-2 ratio was similar to that in the TUNEL-positive ratio. These data, suggest that dynamic changes of the Bax/Bcl-2 ratio might be important in determining point of apoptosis induction in pancreatic cancer cells with p53 mutation.
Department of Surgery and Surgical Basic Science, Kyoto University, Japan. mic@kuhp.kyoto-u.ac.jp
M
M
Wada
R
R
Hosotani
J U
JU
Lee
R
R
Doi
T
T
Koshiba
K
K
Fujimoto
Y
Y
Miyamoto
S
S
Tsuji
S
S
Nakajima
A
A
Okuyama
M
M
Imamura
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D019925:Cyclin A / Q000096:biosynthesis; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000633:toxicity; D019254:Genes, bcl-2 / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D007700:Kinetics; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D019925:Cyclin A; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D051028:bcl-2-Associated X Protein; C082868:butyrolactone I; D018844:Cyclin-Dependent Kinases; D015107:4-Butyrolactone