Chemotherapy triggers apoptosis in a caspase-8-dependent and mitochondria-controlled manner in the non-small cell lung cancer cell line NCI-H460
| Autor: | Cg, Ferreira, Sw, Span, Gj, Peters, Frank Kruyt, Giaccone G |
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| Předmět: |
Antimetabolites
Antineoplastic DNA Complementary Lung Neoplasms Fas-Associated Death Domain Protein Blotting Western bcl-X Protein Antineoplastic Agents Apoptosis Cytochrome c Group Transfection Deoxycytidine Amino Acid Chloromethyl Ketones Inhibitory Concentration 50 Jurkat Cells Cytosol Carcinoma Non-Small-Cell Lung Tumor Cells Cultured Humans Adaptor Proteins Signal Transducing Genes Dominant Caspase 8 Caspase Inhibitors Gemcitabine Caspase 9 Mitochondria Spectrometry Fluorescence Proto-Oncogene Proteins c-bcl-2 Caspases Cisplatin Carrier Proteins Topotecan |
| Zdroj: | University of Groningen Europe PubMed Central |
| Popis: | Chemotherapy-induced apoptosis is generally thought to be dependent on a pathway headed by caspase-9. This model is primarily based on studies performed in leukemia cells; however, little is known about caspase cascades in relatively resistant solid tumor cells, including non-small cell lung cancer (NSCLC) cells. Using the NSCLC cell line NCI-H460 (H460), here, we studied the effect of stable expression of various caspase inhibitors on apoptosis induced by the anticancer drugs cisplatin, topotecan, and gemcitabine. Interestingly, overexpression of caspase-9S and X-linked inhibitor of apoptosis (XIAP), both able to inhibit caspase-9 activity, failed to block apoptosis. In contrast, stable expression of caspase-8 inhibitors, such as cytokine response modifier A (CrmA) and dominant-negative caspase-8, almost completely abrogated apoptosis and also enhanced clonogenic survival. Caspase-8 activation in H460 cells was not mediated by death receptors, inasmuch as overexpression of dominant-negative Fas-associated death domain (FADD-DN) did not prevent procaspase-8 cleavage and subsequent apoptosis. However, stable expression of Bcl-2 and Bcl-xL did suppress these apoptotic events, including the release of cytochrome c from mitochondria, which was observed in drug-treated H460 cells. In the NSCLC cell line H460, we, thus, provide evidence for the existence of a novel drug-inducible apoptotic pathway in which activation of caspase-8, and not of caspase-9, forms the apical and mitochondria-dependent step that subsequently activates the downstream caspases. |
| Databáze: | OpenAIRE |
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