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Doxorubicin-Induced Death in Neuroblastoma Does Not Involve Death Receptors in S-Type Cells and Is Caspase-Independent in N-Type Cells

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Doxorubicin-Induced Death in Neuroblastoma Does Not Involve Death Receptors in S-Type Cells and Is Caspase-Independent in N-Type Cells Oncogene (2002) 21, 6132 – 6137 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells Sally Hopkins-Donaldson1, Pu Yan1, Katia Balmas Bourloud1, Annick Muhlethaler1, Jean-Luc Bodmer2 and Nicole Gross*,1 1Department of Pediatric Onco-Hematology, Centre Hospitalier Universitaire Vaudois, CH1011 Lausanne, Switzerland; 2Institute of Biochemistry, University of Lausanne, CH-1066, Epalinges, Switzerland Death induced by doxorubicin (dox) in neuroblastoma tumors in infants frequently undergo spontaneous (NB) cells was originally thought to occur via the Fas remission. Failure to undergo programmed cell death pathway, however since studies suggest that caspase-8 is a putative mechanism for cancer cell resistance to expression is silenced in most high stage NB tumors, it is chemotherapy, while in contrast spontaneous remission more probable that dox-induced death occurs via a is thought to be a result of increased apoptosis (Oue et different mechanism. Caspase-8 silenced N-type invasive al., 1996). NB cell lines LAN-1 and IMR-32 were investigated for Apoptosis signaling occurs via two different path- their sensitivity to dox, and compared to S-type ways which converge on a common machinery of cell noninvasive SH-EP NB cells expressing caspase-8. All demise that is activated by caspases (Strasser et al., cell lines had similar sensitivities to dox, independently of 2000). The death receptor pathway is activated by caspase-8 expression. Dox induced caspase-3, -7, -8 and ligands of the tumor necrosis factor (TNF) family -9 and Bid cleavage in S-type cells and death was which induce the trimerization of their cognate blocked by caspase inhibitors but not by oxygen radical receptors (Daniel et al., 2001). This aggregation scavenger BHA. In contrast, dox-induced death in N- triggers the recruitment of adaptor protein FADD, type cells was caspase-independent and was inhibited by which in turn binds procaspase-8, inducing its activa- BHA. Dox induced a drop in mitochondrial membrane tion by limited proteolytic cleavage. Effector caspases-3 permeability in all cell lines. Dox-induced death in S- and -7 are subsequently processed and activated, which type cells gave rise to apoptotic nuclei, whereas in N- ultimately results in DNA fragmentation and death. type cells nuclei were non-apoptotic in morphology. The mitochondrial pathway is activated by endoge- Transfection of SH-EP cells with a dominant negative neous stress such as DNA damage and is characterized FADD mutant inhibited TRAIL-induced death, but had by the loss of mitochondrial transmembrane potential no effect on dox-induced apoptosis. These results suggest and the release of cytochrome c from mitochondria that S-type cells undergo apoptosis after dox treatment (Green and Reed, 1998). Cytosolic cytochrome c independently of death receptors, whereas N-type cells triggers the assembly of the apoptosome which recruits are killed by a caspase-independent mechanism. and activates caspase-9 and in turn caspases-3 and -7. Oncogene (2002) 21, 6132 – 6137. doi:10.1038/sj.onc. Anti-apoptotic Bcl-2 family members such as Bcl-2 1205879 inhibit cytochrome c release by modulating the ability of Bax and Bak to facilitate opening of pores in the Keywords: apoptosis; caspases; doxorubicin; caspase-8; outer mitochondrial membrane (Wei et al., 2001). neuroblastoma Crosstalk between the two apoptosis signaling path- ways occurs in some cells when caspase-8 converts an inactive form of Bid into a pro-apoptotic form that Introduction interacts with Bax and induces cytochrome c release (Scaffidi et al., 1999). Neuroblastoma (NB) is a heterogeneous pediatric Recent studies have shown that in addition to cancer derived from the sympathetic nervous system. apoptosis, death receptor and mitochondrial signaling Children over 1 year of age with stage IV NB tumors may activate alternative mechanisms of programmed respond poorly to treatment, with a 5 year survival rate cell death which are caspase-independent (Holler et al., of only 30% (Spix et al., 2001), whereas low stage 2000; Leist and Jaattela, 2001). These alternative mechanisms include necrosis and caspase-independent apoptosis which although are rare events in normal cells may be the prominent mode of death in tumor *Correspondence: N Gross, Department of Pediatric Onco-Hematol- cells which have defects in the two apoptosis signaling ogy, University Hospital Lausanne (CHUV), CH-1011 Lausanne, Switzerland; E-mail: [email protected] pathways. Received 10 April 2002; revised 15 July 2002; accepted 16 July Several years ago, Fulda et al. (1997) reported that 2002 death in NB cells induced by chemotherapeutic drugs Doxorubicin-induced death in neuroblastoma cells S Hopkins-Donaldson et al 6133 including doxorubicin (dox) was triggered via the Fas demonstrating that the involvement of the Fas path- signaling pathway. However, conflicting evidence from way in dox-induced apoptosis is cell type specific. In other laboratories demonstrated that lymphocytes type I cells dox activates both the death receptor and derived from Fas-deficient lpr mice were equally as mitochondrial pathways, whereas in type II cells only sensitive to dox as those from wild type mice (Newton the mitochondrial pathway is activated, explaining why and Strasser, 2000) and transfection of cells with in some cells inhibitors of the death receptor pathway specific inhibitors of the Fas pathway such as cFLIP have no effect on dox-induced death. failed to block dox-induced death (Kataoka et al., If the death receptor pathway is important in dox- 1998). Recently, Fulda et al. (2001) attempted to induced death in NB cells, i.e. they are type I cells, it provide an explanation for these discrepancies by follows that resistance to dox should be conferred by Figure 1 Dox-induced death in NB cells. (a) SH-EP, IMR-32, LAN-1 and Jurkat cells (105 cells/well in 96-well plates) were incu- bated with dox for 48 h. Tetrazolium dye solution (Promega) was then added and the production of blue formazan product pro- duced by viable cells measured at an absorbance of 570nm. Percentage cell viability compared to untreated controls was calculated. Assays were performed at least three times and a representative experiment shown. (b) Cells were treated with 5 mg/ml dox for 24 or 48 h. Thirty mg of cellular NP-40 (1%) extracts were analysed by SDS – PAGE (12%) and Western blotting. Blots were incubated with anti-caspases-3 (Transduction Laboratories), -7 (PharMingen), -8 (MBL), -9 (New England Biolabs) or anti-Bid (R&D) anti- bodies followed by peroxidase-conjugated second antibodies (Nordic). Bound antibodies were detected using chemiluminescence. (c) Cells (105 cells/well in 96-well plates) were incubated with different concentrations of dox for 48 h alone or in the presence of 5 100 mM zVADfmk and cell viability assays were performed as above. (d) Cells (10 cells/well in 96-well plates) were incubated with 5 mg/ml dox for 48 h alone or in the present of 50 mM DEVD-FMK, 50 mM zIETD-FMK or 50 mM LEHD-FMK. Cell viability assays were performed as above. Each condition was performed in quadruplicate and means+s.d.s are shown Oncogene Doxorubicin-induced death in neuroblastoma cells S Hopkins-Donaldson et al 6134 the downregulation of the essential initiator caspase-8 to TNF-related apoptosis inducing-ligand (TRAIL)- or by the expression of a FADD dominant negative induced death (Hopkins-Donaldson et al., 2000). We mutant. The majority of high stage NB tumors and cell also assessed the role of the death receptor pathway in lines of neuronal (N-type) phenotype are in fact dox-induced death of the S-type NB cell line SH-EP silenced for caspase-8 expression by promoter hyper- used previously by Fulda et al. (1998) which are highly methylation, a phenomenon that correlates with sensitive to TRAIL-induced death (Hopkins-Donald- amplification of the N-myc oncogene (Teitz et al., son et al., 2000). Cell viability tests were performed in 2000). N-myc amplification is strongly linked to order to compare the sensitivity to dox-induced death malignancy and chemoresistance in high stage tumors, of N-type and S-type NB cell lines. No differences were and N-type cells are invasive in soft agar assays and observed between N-type and S-type cells in their form tumors when injected subcutaneously into nude sensitivity to dox after 48 h (Figure 1a) or 72 h (data mice (La Quaglia et al., 1996). In contrast, similar to not shown). While the IC50 for dox was 0.5 mg/ml in low stage NB tumors, the substrate adherent (S-type) Jurkat T cells, the three NB cell lines were more cell lines such as SH-EP used by Fulda et al. (1998) are resistant, with IC50 values of between 1 and 5 mg/ml. non-invasive, are not amplified for N-myc, and express Others have observed that dox concentrations as low caspase-8. as 0.5 mg/ml induced death in NB cell lines (Fulda et In the present study we investigated the mechanism al., 1997). This discrepancy with our findings might be of dox-induced death in N-type NB cell lines LAN-1 due to different techniques used to measure cell death, and IMR-32, which are silenced for caspase-8 expres- or to variations in behavior of the same cell lines in sion, amplified for N-myc, and are completely resistant different laboratories. In summary, whereas caspase-8 Figure 2 NB cell death induced by dox involves the mitochondria. (a) NB cells (105 cells/well in 96-well plates) were incubated with 5 mg/ml dox for 48 h alone or in the presence of 50 mM BHA.
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