Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer

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    • I. Paul
    • A.D. Chacko
    • I. Stasik
    • S. Busacca
    • N. Crawford
    • F. McCoy
    • N. McTavish
    • B. Wilson
    • M. Barr
    • K.J. O'Byrne
    • D.B. Longley
    • D.A. Fennell

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    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.

    Documents

    DOI

    Original languageEnglish
    Article numbere449
    Number of pages9
    Pages (from-to)1-9
    JournalCell, Death & Disease
    Journal publication dateDec 2012
    Issue numbernull
    Volume3
    DOIs
    Publication statusPublished - Dec 2012

      Research areas

    • Apoptosis, BAX, BAK, non-small-cell lung cancer, cisplatin resistance, caspase-8

    ID: 5385889