Targeting the Apoptosome for Cancer Therapy

Ledgerwood, Elizabeth C.; Morison, Ian M.

doi:10.1158/1078-0432.ccr-08-1172

Cited by 77 publications

(48 citation statements)

References 70 publications

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“…The mitochondria have been considered to act as a point of integration for apoptotic signals originating from both of these 2 apoptotic pathways. Among various proapoptotic events and factors, the disruption of DY m and release of cyto c are considered critical in mitochondria-mediated apoptosis pathways (34). In this study, silibinin showed a dissipation of DY m in bladder cancer cells as evidenced by JC-1 dye staining, which was accompanied by the release of cyto c from mitochondria to cytosol, as evidenced by immunoblotting, and further activation of downstream effectors caspase-9, caspase-3 and resultant PARP cleavage.…”

Section: Discussionmentioning

confidence: 53%

Chemopreventive and Chemotherapeutic Effects of Intravesical Silibinin against Bladder Cancer by Acting on Mitochondria

Zeng

Sun

et al. 2011

Molecular Cancer Therapeutics

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Intravesical chemotherapy is often used to prevent the recurrence of superficial bladder cancer after transurethral resection. A search for more effective and less toxic intravesical agents is urgently needed. We previously found the in vitro apoptotic effects of silibinin, a natural flavonoid, on high-risk bladder carcinoma cells. Here, we further explored the underlying mechanisms and examined the intravesical efficacy in the prevention and treatment of bladder cancer. Human bladder carcinoma cell line 5637, which has the same molecular features of high-risk superficial bladder cancer, was used as the model system in vitro and in vivo. Autochthonous rat model of bladder cancer induced by intravesical N-methyl-N-nitrosourea (MNU) was used to investigate its intravesical efficacy. Exposure of 5637 cells to silibinin resulted in growth inhibition and induction of caspase-dependent and -independent apoptosis, which was associated with disruption of mitochondrial membrane potential and selective release of cytochrome c, Omi/HtrA2, and apoptosisinducing factor (AIF) from mitochondria. Silibinin also downregulated survivin and caused nuclear translocation of AIF. Oral silibinin suppressed the growth of 5637 xenografts, which was accompanied with the activation of caspase-3, downregulation of survivin, and increased translocation of AIF. Furthermore, intravesical silibinin effectively inhibited the carcinogenesis and progression of bladder cancer in rats initiated by MNU by reducing the incidence of superficial and invasive bladder lesions without any side effects, which was accompanied with proapoptotic effects. These findings identify the in vitro and in vivo antitumor efficacy of silibinin, and suggest silibinin as an effective and novel intravesical agent for bladder cancer.

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Section: Discussionmentioning

confidence: 53%

Chemopreventive and Chemotherapeutic Effects of Intravesical Silibinin against Bladder Cancer by Acting on Mitochondria

Zeng

Sun

et al. 2011

Molecular Cancer Therapeutics

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“…20 Ultimately, many of these stressors damage the mitochondria by causing changes in the permeability of the membranes of this organelle, 21 leading to cytochrome c release and apoptosome formation and activation. 22,23 To understand how VOPP1 was activating apoptosis in SCC cells, we first turned to the hypothesis that VOPP1 may Figure 8 The induction of apoptosis from vesicular overexpressed in cancer prosurvival protein 1 (VOPP1) knockdown seen at 72 h post-siRNA transfection is abrogated with the use of the thiol-antioxidant N-acetyl cysteine (NAC) in a dose-dependent manner. (a) On the left axis, caspase-3/ 7 activity in arbitrary luminescence units is shown for control or VOPP1 siRNAs with or without 2.5 mM NAC in squamous cell carcinoma (SCC)-9 cells.…”

Section: Ros Are Required For Apoptosis In Scc Cells Induced By Vopp1mentioning

confidence: 99%

Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury

Baras

Solomon

Davidson

et al. 2011

Laboratory Investigation

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The vesicular overexpressed in cancer prosurvival protein 1 (VOPP1) gene product (previously known as GASP and ECOP) has a poorly characterized functional role in cancer cells, although its expression levels are known to be elevated in many cancer types. To determine the role that VOPP1 has in human squamous cell carcinoma (SCC), a series of siRNA-mediated expression knockdown experiments were performed in carcinoma-derived model systems with confirmed endogenous VOPP1 overexpression (three SCC-derived cell lines: SCC-9, FaDu, and H2170, as well as the cervical adenocarcinoma HeLa cell line, which has been examined in relevant previous reports). The data indicate that VOPP1 knockdown induces cell death at 72 h post-transfection and this is caused by the induction of apoptosis via the intrinsic pathway. Analysis of microarray gene expression profiling showed that genes whose expression was affected by VOPP1 knockdown exhibited enrichment in annotations of oxidative stress and mitochondrial dysfunction. Reporters of reactive oxygen species (ROS) and mitochondrial membrane potential show that ROS levels become elevated and mitochondrial dysfunction occurs with VOPP1 knockdown at time points before the activation of effector caspases and cell death seen at later time points. Furthermore, the introduction of the antioxidant N-acetyl cysteine was able to abrogate the induction of apoptosis observed with VOPP1 knockdown in a dose-responsive manner. Reporter constructs for NF-kB-mediated transcription are not affected in SCC cell lines by VOPP1 knockdown. Taken together, these data support the hypothesis that VOPP1 overexpression in cancer participates in the control of the intracellular redox state, and that its loss leads to oxidative cellular injury leading to cell death by the intrinsic apoptotic pathway. The vesicular overexpressed in cancer prosurvival protein 1 (VOPP1) gene product, previously known as GASP 1 and ECOP, 2 has been shown to be upregulated in a number of human cancer types, including squamous cell carcinoma (SCC). 3,4 Reports from our group 4 and others 2 have shown that siRNA-mediated knockdown of VOPP1 in cell culture model systems results in cell death, consistent with the notion that VOPP1 overexpression has pro-survival effects in cancer biology. In certain experimental systems, results have suggested that VOPP1 may modulate the NF-kB signaling axis; 2,4,5 however, in a previous report, we had found that this association is not universal among cancer-derived cell lines. 4 Moreover, the localization of the VOPP1 protein to intracellular vesicles 3 makes the model of VOPP1 interaction with cytoplasmic NF-kB proteins problematic. To further elucidate the mechanism of VOPP1 siRNA-mediated cell death in relevant cancer-derived models of VOPP1 overexpression, we report here a series of experiments that: (i) better characterize the apoptotic pathway induced by VOPP1 knockdown in human SCC cell lines, (ii) provide additional evidence that NF-kB does not have a role in apoptosis caused by the loss of VO...

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“…53 Inhibition of apoptosis is one of the key features of cancer and in many cancer types where apaf1 loss is evident. 54 It appears that, similarly, Spalax p53 abrogates the activation of apaf1 as an adaptation to escape hypoxia-induced apoptosis. In addition, we provide evidence indicating that besides apaf1 inactivation, hypoxia upregulates mdm2 levels in SApippalax targeting p53 for degradation.…”

Section: Spalax P53 Is Functionally Biased Against Apaf1 and Towards mentioning

confidence: 99%

The expression of p53-target genes in the hypoxia-tolerant subterranean mole-rat is hypoxia-dependent and similar to expression patterns in solid tumors

2010

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Targeting the Apoptosome for Cancer Therapy

Cited by 77 publications

References 70 publications

Chemopreventive and Chemotherapeutic Effects of Intravesical Silibinin against Bladder Cancer by Acting on Mitochondria

Chemopreventive and Chemotherapeutic Effects of Intravesical Silibinin against Bladder Cancer by Acting on Mitochondria

Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury

The expression of p53-target genes in the hypoxia-tolerant subterranean mole-rat is hypoxia-dependent and similar to expression patterns in solid tumors

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