Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance.
In this study, we asked whether overexpression of caspase-3, a central downstream executioner of apoptotic pathways, might sensitize breast cancer cells with acquired drug resistance (MT1/ADR) to drug-induced apoptosis. As control, we employed caspase-3 negative and caspase-3-transfected MCF-7 cells. Whereas mock-transfected MCF-7 cells were resistant to epirubicin, etoposide and paclitaxel (taxol), the same drugs led to breakdown of nuclear DNA in caspase-3-transfected MCF-7 cells. MT1/ADR cells express low levels of wild type caspase-3 but show defective caspase activation and apoptosis upon drug exposure. These cells also display a less efficient activation of the mitochondrial permeability transition. Caspase-3-transfected MT1/ADR clones showed a 2.8-fold increase in the protein level and a 3.7-fold higher specific enzyme activity. Procaspase-3 overexpression was not toxic and did not affect background apoptosis. Interestingly, procaspase-3-transfected MT1/ADR cells were more sensitive to cytotoxic drugs as compared with vector-transfected controls and DNA fragmentation nearly reached the levels of the original drug sensitive MT1 cells. Thus, overexpression of caspase-3 enhances chemosensitivity especially in situations where activation of the mitochondrial apoptosome is disturbed.
Friedrich
K
K
Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Humboldt University Berlin, 13125 Berlin, Germany.
Wieder
T
T
Von Haefen
C
C
Radetzki
S
S
Jänicke
R
R
Schulze-Osthoff
K
K
Dörken
B
B
Daniel
P T
PT
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053938:DNA Fragmentation; D004273:DNA, Neoplasm; D019008:Drug Resistance, Neoplasm; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004792:Enzyme Precursors; D009363:Neoplasm Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases