Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment.
Apoptosis, a tightly controlled multi-step mechanism of cell death, is important for anti-cancer therapy-based elimination of tumor cells. However, this process is not always efficient. Small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) cells display different susceptibility to undergo apoptosis induced by anticancer treatment. In contrast to SCLC, NSCLC cells are cross-resistant to a broad spectrum of apoptotic stimuli, including receptor stimulation, cytotoxic drugs and gamma-radiation. Since resistance of tumor cells to treatment often accounts for the failure of traditional forms of cancer therapy, in the present study attempts to find a potent broad-range apoptosis inductor, which can kill therapy-resistant NSCLC cells were undertaken and the mechanism of apoptosis induction by this drug was investigated in detail. We found that staurosporine (STS) had cell killing effect on both types of lung carcinomas. Release of cytochrome c, activation of apical and effector caspases followed by cleavage of their nuclear substrates and morphological changes specific for apoptosis were observed in STS-treated cells. In contrast to treatment with radiation or chemotherapy drugs, STS induces mitochondrial dysfunction followed by translocation of AIF into the nuclei. These events preceded the activation of nuclear apoptosis. Thus, in lung carcinomas two cell death pathways, caspase-dependent and caspase-independent, coexist. In NSCLC cells, where the caspase-dependent pathway is less efficient, the triggering of an AIF-mediated caspase-independent mechanism circumvents the resistance of these cells to treatment.
Joseph
Bertrand
B
Institute of Environmental Medicine, Department of Toxicology, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden.
Marchetti
Philippe
P
Formstecher
Pierre
P
Kroemer
Guido
G
Lewensohn
Rolf
R
Zhivotovsky
Boris
B
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D051033:Apoptosis Inducing Factor; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D018288:Carcinoma, Small Cell / Q000473:pathology; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000032:analysis; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000096:biosynthesis / Q000235:genetics; D005420:Flavoproteins / Q000502:physiology*; D005720:Gamma Rays; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology; D008175:Lung Neoplasms / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport; D011836:Radiation Tolerance; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
C494829:AIFM1 protein, human; D000590:Amino Acid Chloromethyl Ketones; D051033:Apoptosis Inducing Factor; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D005420:Flavoproteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D013481:Superoxides; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D019311:Staurosporine