Defective caspase-3 relocalization in non-small cell lung carcinoma.
Many anticancer drugs exert their cytotoxicity through DNA damage and induction of apoptosis. Small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) have different sensitivity to treatment with radiation and chemotherapeutic agents with SCLC being more sensitive than NSCLC both in vitro and in vivo. This difference might be related to the different susceptibility of small and non-small cell lung carcinoma to undergo apoptosis. The aim of this study was to investigate if deficiencies in the apoptotic pathways can explain the intrinsic resistance of NSCLC to anti-cancer treatment. Three different triggers were used to induce apoptosis. Etoposide and gamma-radiation, which are important parts of clinical lung cancer treatment, induce DNA-damage, whereas Fas ligation induces receptor-mediated apoptotic pathways. NSCLC cells were cross-resistant to all treatments, whereas SCLC cells, which do not express pro-caspase-8, were resistant to alphaFas-, but not to DNA-damage-induced apoptosis. Cytochrome c release, activation of caspase-9 and the executioner caspase-3 were observed in both types of lung cancer cells. However, cleavage of known nuclear substrates for caspase-3, such as PARP and DFF45/ICAD, was documented only in the sensitive SCLC cells but not in the resistant NSCLC cells. Moreover, relocalization of active caspase-3 from the cytosol into the nucleus upon treatment was observed only in the SCLC cell line. These results indicate that the inhibition of apoptosis in NSCLC occurs downstream of mitochondrial changes and caspase activation, and upstream of nuclear events.
Joseph
B
B
Institute of Environmental Medicine, Department of Toxicology, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden.
Ekedahl
J
J
Lewensohn
R
R
Marchetti
P
P
Formstecher
P
P
Zhivotovsky
B
B
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D053222:Fas Ligand Protein; D005720:Gamma Rays; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy; D008562:Membrane Glycoproteins / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D003574:Cytochrome c Group; D004792:Enzyme Precursors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019384:Nucleic Acid Synthesis Inhibitors; D011506:Proteins; C109664:caspase-activated DNase inhibitor; D005047:Etoposide; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases