Expression of Inhibitor-of-Apoptosis Protein (IAP) Livin by Neuroblastoma Cells: Correlation with Prognostic Factors and Outcome

2005 ◽  
Vol 8 (6) ◽  
pp. 621-629 ◽  
Author(s):  
Dae-Kwang Kim ◽  
Carlos S. Alvarado ◽  
Carlos R. Abramowsky ◽  
Lubing Gu ◽  
Muxiang Zhou ◽  
...  
Keyword(s):  
Cell Lines ◽  
Prognostic Significance ◽  
Neuroblastoma Cells ◽  
Inhibitor Of Apoptosis ◽  
Primary Tumors ◽  
Inhibitor Of Apoptosis Protein ◽  
Tumor Tissues ◽  
Apoptosis Protein ◽  
Polymerase Chain ◽  
Intermediate Expression

Livin is a recently identified member of the Inhibitor-of-Apoptosis protein (IAP) family of antiapoptosis proteins, and expression has been reported in melanoma and some types of carcinoma. We evaluated livin expression in paraffin-embedded tumor tissue from 68 patients with neuroblastoma (NB) and 7 NB cell lines by immunoperoxidase using an anti-livin monoclonal antibody. Eighteen (26.5%) of the 68 NB tumor tissues showed high livin expression, 36 (53%) showed low-intermediate expression, and 14 (20.5%) were negative. Similarly, 4 NB cell lines showed high livin expression, and 3 showed intermediate expression. In primary NB tissue, livin was observed mainly in tumor neuropil, an extension of tumor cell cytoplasm, and the cytoplasm itself. By reverse transcriptase–polymerase chain reaction, livin expression was confirmed in all 7 NB lines and in frozen tissue from 1 of 3 primary tumors examined to date, in agreement with immunohistochemical data; both livin α and β isoforms were detected. In the NB cases, we further analyzed the correlation between livin expression and clinical and biological features with established prognostic significance (i.e., age at diagnosis, stage, histology, and MYCN oncogene status), and patients' outcome. Livin expression alone did not appear to have an effect on survival; however, patients with high livin expression and amplified MYCN had significantly decreased survival compared with patients lacking both markers or with either of these markers alone. These results suggest that (a) livin is expressed in primary and cultured neuroblastoma cells and (b) high livin expression may identify a subset of neuroblastoma patients with a particularly poor prognosis among those with MYCN amplified tumors.

The usefulness of serum X-linked inhibitor of apoptosis protein (XIAP) for predicting recurrence of renal cell carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15055-e15055
Author(s):  
Fumiya Hongo ◽  
Daisuke Toiyama ◽  
Takashi Ueda ◽  
Yasunori Kimura ◽  
Terukazu Nakamura ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Histological Grade ◽  
Cell Cancer ◽  
Prognostic Significance ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inhibitor Of Apoptosis ◽  
Blood Samples ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein

e15055 Background: The X-linked Inhibitor of Apoptosis protein (XIAP) is associated with cell survival by blocking caspase-mediated apoptosis. We have reported the expression and prognostic value of XIAP in human prostate cancer using prostate tissue microarrays (Clin Cancer Res 2007). The expression and prognostic significance of XIAP in renal cell cancer (RCC) has been rarely studied. To our knowledge, no report on the serum XIAP levels from RCC patients has been published. In this study, we examined serum XIAP levels of RCC patients and normal individuals and evaluated its utility as biomarker. Methods: Peripheral blood samples were obtained from 99 patients (68 men and 31 women, median age; 60.7 years [36-85]) with RCC before surgery. All the patients underwent radical or partial nephrectomy. Blood samples were also collected from 52 healthy controls. The histological grade was as follows: grade 1; n= 5, grade 2; n=72, grade 3; n= 22. The serum XIAP levels were measured by a sandwich enzyme-linked immunosorbent assay. Cut off value was calculated by ROC analysis. Results: The serum XIAP levels in patients with RCC were higher than those of normal control individuals (328.3 pg/ml vs 156.2 pg/ml, p<0.001). At a median follow up of 33 months (1-105M), tumor with low serum XIAP showed significantly longer progression free survival (PFS) than those with high serum XIAP in grade 1-2 group (p<0.001). Conclusions: Serum XIAP level is associated with recurrence and prognosis. These results suggest that it may be used as a novel prognosticator and a potential target for renal cell cancer diagnosis and therapy.

Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgi in hematopoietic cells undergoing differentiation: a nuclear export signal-mediated event

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 2035-2043 ◽  
Author(s):  
Stéphanie Plenchette ◽  
Séverine Cathelin ◽  
Cédric Rébé ◽  
Sophie Launay ◽  
Sylvain Ladoire ◽  
...  
Keyword(s):  
Cell Lines ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
B Cell Lymphoma ◽  
Site Directed Mutagenesis ◽  
Inhibitor Of Apoptosis ◽  
Monocytic Cell ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Export Signal

Abstract The caspase inhibitor and RING finger-containing protein cellular inhibitor of apoptosis protein 1 (c-IAP1) has been shown to be involved in both apoptosis inhibition and signaling by members of the tumor necrosis factor (TNF) receptor family. The protein is regulated transcriptionally (eg, is a target for nuclear factor-κB [NF-κB]) and can be inhibited by mitochondrial proteins released in the cytoplasm upon apoptotic stimuli. The present study indicates that an additional level of regulation of c-IAP1 may be cell compartmentalization. The protein is present in the nucleus of undifferentiated U937 and THP1 monocytic cell lines. When these cells undergo differentiation under phorbol ester exposure, c-IAP1 translocates to the cytoplasmic side of the Golgi apparatus. This redistribution involves a nuclear export signal (NES)-mediated, leptomycin B-sensitive mechanism. Using site-directed mutagenesis, we localized the functional NES motif in the caspase recruitment domain (CARD) of c-IAP1. A nucleocytoplasmic redistribution of the protein was also observed in human monocytes as well as in tumor cells from epithelial origin when undergoing differentiation. c-IAP1 does not translocate from the nucleus of cells whose differentiation is blocked (ie, in cell lines and monocytes from transgenic mice overexpressing B-cell lymphoma 2 [Bcl-2] and in monocytes from patients with chronic myelomonocytic leukemia). Altogether, these observations associate c-IAP1 cellular location with cell differentiation, which opens new perspectives on the functions of the protein. (Blood. 2004;104:2035-2043)

YM155, a Survivin Suppressant, Induces Cell Death Via Suppression Of c-Myc Expression In Multiple Myeloma Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1667-1667
Author(s):  
Shigeki Ito ◽  
Maki Asahi ◽  
Ryousei Sasaki ◽  
Tatsuo Oyake ◽  
Hideto Tamura ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Conflicts Of Interest ◽  
Mrna Level ◽  
Inhibitor Of Apoptosis ◽  
Dependent Manner ◽  
Myeloma Cells ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein

Abstract Survivin is a member of the inhibitor of apoptosis protein (IAP) family with its dual roles in mitosis and apoptosis, and emerges as an attractive target for cancer therapy. Recent reports have demonstrated that survivin overexpression is associated with drug resistance and poor outcome in hematological malignancy including multiple myeloma (MM). YM155, a novel molecular targeted agent, suppresses survivin through the inhibition of transcription. However, the effect of this agent on MM cells has not been elucidated. In this study, we investigated the effect of YM155 on proliferation and survival of five human MM cell lines. YM155 inhibited the proliferation of these cells in a dose- and time-dependent manner (IC50 = 10 nM in 3 and 100 nM in 2 cell lines, respectively). Annexin V assay showed that YM155 induced apoptosis in these cells. To better understand these effects of YM155 on MM cells, we evaluated the intracellular signaling and apoptosis-associated protein status. Immunoblot analyses showed that YM155 reduced not only survivin but also myeloid cell leukemia sequence 1 (Mcl-1) and X-linked inhibitor of apoptosis protein (XIAP) expression. We also observed the activation of caspase-3 and poly(ADP-ribose) polymerase in YM155-treated cells, indicating that YM155 induces caspase-dependent apoptosis. YM155 did not affect phosphorylation status of Erk1/2 and STAT3. Interestingly, we found that YM155 suppressed c-Myc and interferon regulatory factor 4 (IRF4) expression, both of which are recognized as an important oncogene in the pathogenesis of MM. In addition, c-Myc and IRF4 protein levels were reduced at 6 and 12 hours after treatment with YM155, respectively. As IRF4 and c-Myc form a positive feedback loop in myeloma cells, this observation indicates that c-Myc inhibition by YM155 treatment might lead to subsequent inhibition of IRF4 expression, and thus raises the possibility of YM155 target for c-Myc rather than IRF4. We next examined the mechanism of downregulation of c-Myc in RPMI8226 cells. Real-time quantitative RT-PCR assay showed that YM155 treatment reduced c-Myc mRNA level. On the other hand, proteasome inhibitor did not prevent the suppression of c-Myc expression by YM155 treatment. These Results suggest that YM155 transcriptionally at least in part represses c-Myc in RPMI8226 cells. In conclusion, YM155 suppresses cell proliferation and survival in MM cells in part via not only inhibiting anti-apoptotic proteins such as survivin, Mcl-1 and XIAP but also repressing c-Myc oncogene. Further study is needed to clarify the molecular mechanism of downregulation of c-Myc induced by YM155. Our Results may provide a platform for clinical trials of YM155 in MM. Disclosures: No relevant conflicts of interest to declare.

The usefulness of serum X-linked inhibitor of apoptosis protein (XIAP) for predicting recurrence of renal cell carcinoma.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 396-396
Author(s):  
Fumiya Hongo ◽  
Daisuke Toiyama ◽  
Takashi Ueda ◽  
Yasunori Kimura ◽  
Terukazu Nakamura ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Histological Grade ◽  
Cell Cancer ◽  
Prognostic Significance ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inhibitor Of Apoptosis ◽  
Blood Samples ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein

396 Background: The X-linked Inhibitor of Apoptosis protein (XIAP) is associated with cell survival by blocking caspase-mediated apoptosis. We have reported the expression and prognostic value of XIAP in human prostate cancer using prostate tissue microarrays (Clin Cancer Res 2007). The expression and prognostic significance of XIAP in renal cell cancer (RCC) has been rarely studied. To our knowledge, no report on the serum XIAP levels from RCC patients has been published. In this study, we examined serum XIAP levels of RCC patients and normal individuals and evaluated its utility as biomarker. Methods: Peripheral blood samples were obtained from 99 patients (68 men and 31 women, median age; 60.7 years [36–85]) with RCC before surgery. All the patients underwent radical or partial nephrectomy. Blood samples were also collected from 52 healthy controls. The histological grade was as follows: Grade1; n= 5, Grade2; n=72, Grade3; n= 22. The serum XIAP levels were measured by a sandwich enzyme-linked immunosorbent assay. Cut off value was calculated by ROC analysis. Results: The serum XIAP levels in patients with RCC were higher than those of normal control individuals (328.3 pg/ml vs 156.2 pg/ml, P<0.001). At a median follow up of 33 months (1-105M), tumor with low serum XIAP showed significantly longer progression free survival (PFS) than those with high serum XIAP in Grade 1-2 group (P<0.001). Conclusions: Serum XIAP level is associated with recurrence and prognosis. These results suggest that it may be used as a novel prognosticator and a potential target for renal cell cancer diagnosis and therapy.

Sign in / Sign up

Export Citation Format

Share Document