title: Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer.
abstract: Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK.
authors.forename: I
authors.initials: I
authors.lastname: Paul
authors.forename: A D
authors.initials: AD
authors.lastname: Chacko
authors.forename: I
authors.initials: I
authors.lastname: Stasik
authors.forename: S
authors.initials: S
authors.lastname: Busacca
authors.forename: N
authors.initials: N
authors.lastname: Crawford
authors.forename: F
authors.initials: F
authors.lastname: McCoy
authors.forename: N
authors.initials: N
authors.lastname: McTavish
authors.forename: B
authors.initials: B
authors.lastname: Wilson
authors.forename: M
authors.initials: M
authors.lastname: Barr
authors.forename: K J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: D B
authors.initials: DB
authors.lastname: Longley
authors.forename: D A
authors.initials: DA
authors.lastname: Fennell
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects
chemical_list: D053181:Caspase 8; D002945:Cisplatin