Influence of Bcl-2 overexpression on the ceramide pathway in daunorubicin-induced apoptosis of leukemic cells

Allouche, Michèle; Bettaieb, Ali; Vindis, Cécile; Rousse, A.; Grignon, Cécile; Laurent, Guy

doi:10.1038/sj.onc.1201023

Cited by 70 publications

(51 citation statements)

References 23 publications

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“…In contrast, some recent studies have shown that Bcl-2 overexpression did not a ect ceramide accumulation in response to certain anti-cancer drugs Allouche et al, 1997) or receptor agonists (Dbaibo et al, 1997, Wiesner et al, 1997. However, in these individual studies, only a single overexpressing clone was used and there is no precise assessment regarding the expression levels of Bcl-2 or Bcl-xL.…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies have shown that the inhibition of ceramide accumulation by Bcl-2 overexpression during apoptosis induced by chemotherapeutic agents, irradiation, or hypoxia (Yoshimura et al, 1998;Tepper et al, 1999). In contrast, other studies have demonstrated that overexpression of Bcl-2 or Bcl-xL failed to prevent ceramide formation in response to certain anti-cancer drugs Allouche et al, 1997) or receptor agonists (Dbaibo et al, 1997;Wiesner et al, 1997). At present, therefore, the mechanism underlying the Bcl-2-mediated protection against the ceramide signaling pathway is still controversial.…”

Section: Introductionmentioning

confidence: 99%

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Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

et al. 2000

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Ceramide has recently been regarded as a potential mediator of apoptosis. In the present study, the e ects of Bcl-2 and Bax on the ceramide-mediated apoptotic pathways were examined in glioma cells overexpressing Bcl-2 or Bax. Etoposide, cisplatin and tumor necrosis factor-a induced apoptosis of C6 rat glioma cells which was associated with ceramide formation due to activation of neutral sphingomyelinase, followed by release of mitochondrial cytochrome c into the cytosol and activation of caspases-9 and -3. The growth of C6 cells stably overexpressing either Bcl-2 or Bax was almost equal to that of the vector-transfected cells. Bax overexpression enhanced etoposide-induced apoptosis through acceleration of cytochrome c release and caspases activation. However, Bax had no e ect on ceramide formation. Similar ®ndings were obtained in C6 cells and U87-MG human glioblastoma cells which were transiently overexpressed with Bax. In contrast, Bcl-2 overexpression resulted in a retardation of the apoptotic process via prevention of cytochrome c release and caspases activation, and ceramide formation was also blocked when Bcl-2 was highly overexpressed in glioma cells. In addition, transient overexpression of Bcl-xL also exerted inhibitory e ects on ceramide formation and apoptotic cell death induced by etoposide. These results indicate that Bax promotes apoptosis regardless of ceramide formation and that Bcl-2 or Bcl-xL prevents ceramide formation by repressing neutral sphingomyelinase as well as ceramide-induced cytochrome c release.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

et al. 2000

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“…However, NPM-ALK delayed rather than completely abrogated cell death. Interestingly, known antiapoptotic genes, such as Bcl-2 (Yin and Schimke, 1995;Allouche et al, 1997) and BCR-ABL (Dubrez et al, 1998) also induce a delay in drug-induced apoptosis. Therefore, our results indicate that NPM-ALK acts as an antiapoptotic gene, as suggested also by its ability to confer cytokineindependent growth to the murine interleukin 3-dependent BaF3 cell line (Bai et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Expression of the oncogenic NPM-ALK chimeric protein in human lymphoid T-cells inhibits drug-induced, but not Fas-induced apoptosis

et al. 2001

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Anaplastic large cell lymphomas (ALCLs) are frequently associated with the t(2;5)(p23;q35) translocation, leading to the expression of NPM-ALK, a fusion protein linking nucleophosmin and anaplastic lymphoma kinase, a receptor tyrosine kinase. In ALCLs, dimerization of NPM-ALK leads to constitutive autophosphorylation and activation of the kinase, necessary for NPM-ALK oncogenicity. To investigate whether NPM-ALK, like other oncogenic tyrosine kinases, can inhibit druginduced apoptosis, we permanently transfected NPM-ALK into Jurkat T-cells. As in ALCLs, NPM-ALK was expressed as a constitutively kinase-active 80 kDa protein, and could be detected by immunocytochemistry in nucleoli, nuclei and cytoplasm. Doxorubicin-induced apoptosis (assessed by cell morphology and annexin V-FITC binding) was signi®cantly inhibited in two independent NPM-ALK-expressing clones (5.2+1.8 and 7.5+0.8% apoptosis), compared to control vectortransduced cells (36+6.7%). Similar results were observed with etoposide. In contrast, Fas-induced apoptosis was not inhibited. Cytochrome c release into the cytosol was delayed in doxorubicin-, but not antiFas-treated transfectant cells, indicating that apoptosis inhibition occurred upstream of mitochondrial events. Using NPM-ALK mutants, we demonstrated that inhibition of drug-induced apoptosis: (1) requires functional kinase activity, (2) does not involve phospholipase C-g, essential for NPM-ALK-mediated mitogenicity and (3) appears to be phosphoinositide 3-kinase independent, despite a strong Akt/PKB activation observed in wild type NPM-ALK-expressing cells. These results suggest that the NPM-ALK antiapoptotic and mitogenic pathways are distinct. Oncogene (2001) 20, 7386 ± 7397.

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“…Nevertheless, it seems unlikely that such differences (if any) may account for the lack of CER generation in TF-1-34 cells. Indeed, as far as Bcl-2 is concerned, several recent reports demonstrated that Bcl-2 blocked CER-induced apoptosis but did not interfere with CER generation induced by cytotoxic agents (Martin et al, 1995;Zhang et al, 1996;Smith et al, 1996;Allouche et al, 1997). As far as p53 is concerned, it should be noted that a mutated p53 gene has been documented in the parental TF-1 cell line (Sugimoto et al, 1992), and we have confirmed altered p53 mRNA in both TF-1-34 and TF-1-33 by reverse transcriptase-polymerase chain reaction single-strand conformational polymorphism analysis (Jaffre Â zou J.P., Bruno A.P.…”

Section: Discussionmentioning

confidence: 99%

Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation

et al. 1998

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The mechanism(s) by which ionizing radiation (IR) induces cell death is of fundamental importance in understanding cell sensitivity and resistance. Here we evaluated the response to IR of two subclones of the autonomous human erythromyeloblastic cell line TF-1: TF-1-34 (which expresses CD34) and TF-1-33 (which lacks CD34). In clonogenic assays, TF-1-34 cells were found to be relatively less sensitive to IR compared to TF-1-33 cells based on the D 0 determination (3.01 vs 1.56 Gy). Furthermore, after IR at 12 Gy, TF-1-33 cell viability decreased by *50% within 24 h, whereas TF-1-34 cell growth was unaffected during this time. Gradual loss of TF-1-34 cell viability was observed only after 48 h. Morphological and molecular analysis revealed that TF-1-33 cells died of apoptosis, and TF-1-34 cells of delayed reproductive cell death. While IR produced comparable amounts of DNA double strand breaks (DSB) in both cell lines, TF-1-34 retained DSB much longer than TF-1-33 suggesting that radioresistance and the defective apoptotic response of TF-1-34 cells was not related to a higher DNA repair capacity. However, the lack of an apoptotic response in TF-1-34 was correlated to the absence of a sphingomyelin (SM)-ceramide (CER) signaling pathway. Indeed, IR triggered in TF-1-33 cells but not in TF-1-34, SM hydrolysis (25% at 12 Gy) and CER generation (450%) through the activation of neutral but not acid sphingomyelinase. Synthetic cell permeate CER induced apoptosis in both TF-1-33 and TF-1-34 cells. This study indicates that alterations of the SM-CER signaling pathway can significantly influence the cell death process as well as the survival of acute myeloid leukemia cells after IR exposure.

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Influence of Bcl-2 overexpression on the ceramide pathway in daunorubicin-induced apoptosis of leukemic cells

Cited by 70 publications

References 23 publications

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells

Expression of the oncogenic NPM-ALK chimeric protein in human lymphoid T-cells inhibits drug-induced, but not Fas-induced apoptosis

Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation

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