The differential sensitivity of Bc1-2-overexpressing human breast tumor cells to TRAIL or doxorubicin-induced apoptosis is dependent on Bc1-2 protein levels.
Bc1-2 protein is a potent anti-apoptotic protein that inhibits a mitochondria-operated pathway of apoptosis in many cells. DNA damaging agents and death receptor ligands can activate this mitochondrial apoptotic mechanism. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been suggested to escape from the inhibitory action of Bc1-2 protein. We show that in human breast tumor MCF-7 cells, TRAIL induced a mitochondrial pathway of apoptosis that involved cytochrome c release from mitochondria and activation of caspase 9. The DNA damaging drug doxorubicin also activated this mitochondria-regulated mechanism of apoptosis, which was inhibited in Bc1-2-overexpressing cells. We also demonstrate that in MCF-7 cells Bc1-2 might confer resistance to TRAIL-induced apoptosis, depending on the expression levels of the anti-apoptotic protein. These results indicate that enhanced expression of Bc1-2 in tumor cells can render these cells less sensitive not only to chemotherapeutic drugs but also to TRAIL.
Ruiz de Almodóvar
C
C
Instituto de Parasitología y Biomedicina CSIC, calle Ventanilla 11, 18001 Granada, Spain.
Ruiz-Ruiz
C
C
Muñoz-Pinedo
C
C
Robledo
G
G
López-Rivas
A
A
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014404:Tubulin / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D003574:Cytochrome c Group; D004273:DNA, Neoplasm; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014404:Tubulin; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases