Erythroid differentiation sensitizes K562 leukemia cells to TRAIL-induced apoptosis by downregulation of c-FLIP

Ville Hietakangas, Minna Poukkula, Kaisa M Heiskanen, Jarkko T Karvinen, Lea Sistonen, John E Eriksson

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

Regulation of the apoptotic threshold is of great importance in the homeostasis of both differentiating and fully developed organ systems. Triggering differentiation has been employed as a strategy to inhibit cell proliferation and accelerate apoptosis in malignant cells, in which the apoptotic threshold is often characteristically elevated. To better understand the mechanisms underlying differentiation-mediated regulation of apoptosis, we have studied death receptor responses during erythroid differentiation of K562 erythroleukemia cells, which normally are highly resistant to tumor necrosis factor (TNF) alpha-, FasL-, and TRAIL-induced apoptosis. However, upon hemin-mediated erythroid differentiation, K562 cells specifically lost their resistance to TNF-related apoptosis-inducing ligand (TRAIL), which efficiently killed the differentiating cells independently of mitochondrial apoptotic signaling. Concomitantly with the increased sensitivity, the expression of both c-FLIP splicing variants, c-FLIP(L) and c-FLIP(S), was downregulated, resulting in an altered caspase 8 recruitment and cleavage in the death-inducing signaling complex (DISC). Stable overexpression of both c-FLIP(L) and c-FLIP(S) rescued the cells from TRAIL-mediated apoptosis with isoform-specific effects on DISC-recruited caspase 8. Our results show that c-FLIP(L) and c-FLIP(S) potently control TRAIL responses, both by distinct regulatory features, and further imply that the differentiation state of malignant cells determines their sensitivity to death receptor signals.

OriginalspråkEngelska
Sidor (från-till)1278-91
Antal sidor14
TidskriftMolecular and Cellular Biology
Volym23
Nummer4
DOI
StatusPublicerad - feb. 2003
MoE-publikationstypA1 Tidskriftsartikel-refererad

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