Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release

Park, Moon Taek; Kim, Min Jung; Kang, Young Jong; Choi, Sang Sam; Lee, Jae Hoon; Choi, Jung A.; Kang, Chang Mo; Cho, Chul Koo; Kang, Seongman; Bae, Sangwoo; Lee, Yun Sil; Chung, Hee Yong; Lee, Su Jae

doi:10.1182/blood-2004-07-2938

Cited by 119 publications

(95 citation statements)

References 70 publications

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“…Thus, recombinant AIF induces marked pyknosis when added to isolated nuclei or when microinjected into intact cells Loeffler et al, 2001). Moreover, the injection of AIF-neutralizing antibodies or the knockdown of AIF expression with small interfering RNAs has established that endogenous AIF is rate limiting for caspase-independent chromatin condensation induced by apoptotic stimuli (Cregan et al, 2002;Gallego et al, 2004;Kang et al, 2004;Cheung et al, 2005;Park et al, 2005). Condensation of DNA is also documented in vitro, when AIF is added to naked DNA, as shown in this paper.…”

Section: Aif Interactions With Nucleic Acids N Vahsen Et Almentioning

confidence: 52%

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Physical interaction of apoptosis-inducing factor with DNA and RNA

et al. 2005

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Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein, which upon apoptosis induction translocates to the nucleus where it interacts with DNA by virtue of positive charges clustered on the AIF surface. Here we show that the AIF interactome, as determined by mass spectroscopy, contains a large panel of ribonucleoproteins, which apparently bind to AIF through the RNA moiety. However, AIF is devoid of any detectable RNAse activity both in vitro and in vivo. Recombinant AIF can directly bind to DNA as well as to RNA. This binding can be visualized by electron microscopy, revealing that AIF can condense DNA, showing a preferential binding to singlestranded over double-stranded DNA. AIF also binds and aggregates single-stranded and structured RNA in vitro. Single-stranded poly A, poly G and poly C, as well doublestranded A/T and G/C RNA competed with DNA for AIF binding with a similar efficiency, thus corroborating a computer-calculated molecular model in which the binding site within AIF is the same for distinct nucleic acid species, without a clear sequence specificity. Among the preferred electron donors and acceptors of AIF, nicotine adenine dinucleotide phosphate (NADP) was particularly efficient in enhancing the generation of higher-order AIF/ DNA and AIF/RNA complexes. Altogether, these data support a model in which a direct interaction of AIF contributes to the compaction of nucleic acids within apoptotic cells.

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Section: Aif Interactions With Nucleic Acids N Vahsen Et Almentioning

confidence: 52%

“…On the one hand, AIF is required for the growth of colon carcinoma cells (Urbano et al, 2005). On the other hand, AIF is required for experimental apoptosis induction, for instance in radiation-resistant human T-cell lymphoma (Park et al, 2005) or in lung or cervix carcinoma (Gallego et al, 2004;Kang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Physical interaction of apoptosis-inducing factor with DNA and RNA

et al. 2005

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“…13,35 Experiments using antioxidants further indicate that ROS acts upstream of Bax relocation and mitochondrial depolarization. 13 We observed that NAC substantially inhibited ROS production, upregulation of p53, conformational changes of Bax, disruption of the DC m , and cell death induction. Nuclear localization of cytochrome c, AIF, and EndoG was detected in all 4-OOH-CY-treated apoptotic cells.…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear relocation of mitochondrial factors is often preceded by drug-mediated induction of reactive oxygen species (ROS) followed by mitochondrial relocalization of Bax and subsequent mitochondrial disintegration. 13 Cyclophosphamide (CY), a DNA-damaging agent inducing interstrand DNA cross-links, is used in the treatment of lymphomas and autoimmune diseases. 14 CY is a prodrug, which is converted into its active form 4-hydroxy-cyclophosphamide in the liver.…”

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confidence: 99%

4-hydroperoxy-cyclophosphamide mediates caspase-independent T-cell apoptosis involving oxidative stress-induced nuclear relocation of mitochondrial apoptogenic factors AIF and EndoG

et al. 2007

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Apoptosis is a major mechanism of treatment-induced T-cell depletion in leukemia and autoimmune diseases. While 'classical' apoptosis is considered to depend on caspase activation, caspase-independent death is increasingly recognized as an alternative pathway. Although the DNA-damaging drug cyclophosphamide (CY) is widely used for therapy of hematological malignancies and autoimmune disorders, the molecular mechanism of apoptosis induction remains largely unknown. Here, we report that treatment of Jurkat, cytotoxic, and primary leukemic T cells with an activated analog of CY, 4-hydroperoxycyclophosphamide (4-OOH-CY), induces caspase activation and typical features of apoptosis, although cell death was not prevented by caspase inhibition. Also depletion of murine thymocytes and splenocytes after CY treatment in vivo was not inhibited by Z-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD.fmk). Caspase-8 and receptor-induced protein (RIP) were dispensable for 4-OOH-CY-mediated apoptosis, while overexpression of Bcl-2 was partially protective. 4-OOH-CY treatment induced reactive oxygen species production, upregulation of Bax, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor (AIF) and endonuclease G (EndoG). The antioxidant N-acetyl-L-cysteine substantially inhibited conformational changes of Bax, loss of mitochondrial membrane potential, nuclear relocation of mitochondrial factors, and apoptosis induction in 4-OOH-CYtreated T cells. These results strongly indicate that oxidative damage-induced nuclear translocation of AIF and EndoG in 4-OOH-CY-treated T cells might represent an alternative death pathway in the absence of caspase activity.

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“…10 In mammalian cells, removal of AIF can reduce apoptosis in some particular settings, although there is no general apoptosis defect. 2,8,9 Thus, knockdown of AIF protects differentiated PC12 cells against the neurotoxin 1-methyl-4-phenylpyridinium, 12 Jurkat T lymphoma cells against a combination of g-irradiation and phytosphingosin, 13 16 and Raji B lymphoma cells against UV irradiation. 17 Microinjection of AIF-neutralizing antibodies can also reduce the neurotoxic effects of NMDA in primary murine cortical cultures, 18 the lethal effects of PARP-1 activators in several cellular systems, 19 as well as the proapoptotic effects of staurosporin on non-small cell lung carcinoma cells.…”

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confidence: 94%