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Endoplasmic reticulum stress in the proapoptotic action of edelfosine in solid tumor cells

AuthorsNieto-Miguel, Teresa; Fonteriz, Rosalba I. ; Vay, Laura; Gajate, Consuelo; López-Hernández, Silvia; Mollinedo, Faustino
Issue Date2007
PublisherAmerican Association for Cancer Research
CitationCancer Research 67(21): 10368-10378 (2007)
AbstractThe endoplasmic reticulum (ER) has been posited as a potential anticancer target. The synthetic antitumor alkyl-lysophospholipid analogue edelfosine accumulates in the ER of solid tumor cells. This ER accumulation of the drug leads to the inhibition of phosphatidylcholine and protein synthesis, G 2-M arrest, depletion of ER-stored Ca2+, Bax up-regulation and activation, transcriptional factor growth arrest and DNA damage-inducible gene 153 up-regulation, caspase-4 and caspase-8 activation, and eventually to apoptosis. Edelfosine prompted ER stress apoptotic signaling, but not the survival unfolded protein response. Edelfosine also induced persistent c-Jun NH2-terminal kinase (JNK) activation. Gene transfer-mediated overexpression of apoptosis signal-regulating kinase 1, which plays a crucial role in ER stress, enhanced edelfosine-induced JNK activation and apoptosis. Inhibition of JNK, caspase-4, or caspase-8 activation diminished edelfosine-induced apoptosis. Edelfosine treatment led to the generation of the p20 caspase-8 cleavage fragment of BAP31, directing proapoptotic signals between the ER and the mitochondria. bax-/-bak-/- double-knockout cells fail to undergo edelfosine-induced ER-stored Ca2+ release and apoptosis. Wild-type and bax-/-bak-/- cells showed similar patterns of phosphatidylcholine and protein synthesis inhibition, despite their differences in drug sensitivity. Thus, edelfosine-induced apoptosis is dependent on Bax/Bak-mediated ER-stored Ca2+ release, but phosphatidylcholine and protein synthesis inhibition is not critical. Transfection-enforced expression of Bcl-XL, which localizes specifically in mitochondria, prevented apoptosis without inhibiting ER-stored Ca2+ release. These data reveal that edelfosine induces an ER stress response in solid tumor cells, providing novel insights into the edelfosine-mediated antitumor activity. Our data also indicate that mitochondria are indispensable for this edelfosine-induced cell death initiated by ER stress. ©2007 American Association for Cancer Research.
Identifiersdoi: 10.1158/0008-5472.CAN-07-0278
issn: 0008-5472
e-issn: 1538-7445
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