Overexpression of Bax sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents.
OBJECTIVE
Bax plays an important role in the regulation of apoptosis induced by chemotherapy and other stimuli. We therefore investigated the role of Bax in drug-induced apoptosis in human pancreatic cancer cells.


METHODS
A tetracycline-inducible retroviral expression vector bearing the human bax-alpha gene was constructed. ASPC-1 cells were stably infected with this vector. The sensitivity of the transformed cell line to gemcitabine and 5-Fu was assessed.


RESULTS
Western blots revealed that Bax expression was enhanced in these cells by the tetracycline analogue doxycycline. Enhanced expression of Bax itself did not inhibit the growth rate of infected cells and did not influence expression of Bcl-2 and Bcl-xL. However, it significantly increased the sensitivity of cells to the chemotherapeutic drugs gemcitabine and 5-Fu. These drugs also activated caspase-8 and caspase-3 by up to ninefold. Caspase activation and/or an imbalance in Bax and Bcl-2/Bcl-xL expression may be the reasons for the augmentation of cytotoxicity by these drugs.


CONCLUSIONS
The findings suggest that enhanced Bax expression may have therapeutic application in enhancing the efficacy of chemotherapy in pancreatic cancers.
Xu
Zhong-Wei
ZW
Department of Clinical Pharmacology, University of Berne, Murtenstrasse 35, 3010 Berne, Switzerland.
Friess
Helmut
H
Büchler
Markus W
MW
Solioz
Marc
M
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007211:Indoles; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D013754:Tetracyclines; D014162:Transfection; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000093542:Gemcitabine
D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D007211:Indoles; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013754:Tetracyclines; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003841:Deoxycytidine; C007293:DAPI; D012264:Ribonucleotide Reductases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D005472:Fluorouracil; D000093542:Gemcitabine