Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent

Hurwitz, Jane; Stasik, Izabela; Kerr, Emma; Holohan, Caitriona; Redmond, Keara L.; McLaughlin, Kylie A.; Busacca, Sara; Barbone, Dario; Broaddus, V. Courtney; Gray, Steven G.; O’Byrne, K.J.; Johnston, Patrick G.; Fennell, Dean A.; Longley, Daniel B.

doi:10.1016/j.ejca.2011.11.009

Cited by 37 publications

(39 citation statements)

References 48 publications

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“…New therapeutic agents are required for MPM patients. HDAC inhibitors are emerging as candidate therapeutic agents in this arena based on the results of in vitro and in vivo studies (6,7). In our study, high levels of IL-18 were found in PEM-and SAHA-resistant MPM cell lines.…”

Section: Discussionmentioning

confidence: 87%

“…Therefore, new therapeutic modalities that have clinically beneficial effects are urgently required for appropriate management of MPM patients. Recently, the histone deacetylase (HDAC) inhibitor, vorinostat (SAHA), significantly enhanced CDDP-induced apoptosis in MPM cells (6). In addition, the HDAC inhibitor, valproate, in combination with CDDP and PEM, provided additional efficacy in respect to treatment of MPM cell line-derived xenografts in vivo (7).…”

Section: Introductionmentioning

confidence: 99%

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miR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma

et al. 2014

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Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence in Japan. In this study, we performed gene and microRNA (miRNA) expression profiling to identify novel therapeutic targets in MPM cells. Based on relative sensitivities to pemetrexed (PEM) and the histone deacetylase (HDAC) inhibitor, vorinostat (SAHA), 211H cells were determined to be the only sensitive MPM cell line out of the 6 tested. On the same series of cell lines, we performed whole genome transcriptomic profiling via DNA microarrays and pathway analysis of the derived data. Of particular note, IL-18 gene expression levels were significantly higher in the cell lines that were either drug resistant or displayed intermediate sensitivity, compared to the sensitive 211H cell line. Pathway analysis revealed IL-18 as an important gene associated with drug sensitivity of MPM cells. A relationship between IL-18 overexpression and drug resistance was also observed following targeted assessment of 10 cytokine genes using quantitative RT-PCR. miRNA expression profiles were evaluated in the MPM cell line panel in order to discern the mechanism of IL-18 induction in the drug-resistant lines. We found that miR-379 and miR-411 belonged to the same cluster of miRNAs located on chromosome 14q32 that commonly target the IL-18 gene. Luciferase reporter assays revealed that miR-379 and miR-411 directly target the IL-18 gene. Introduction of miR-379 plus miR-411, as well as IL-18 silencing, significantly suppressed the invasive capacity of MESO1 cells in vitro. Furthermore, the use of either PEM or SAHA together with miR-379 plus miR-411 mimics mediated increased sensitivity to these drugs in MESO1 cells. These results suggest that the miR-379/411 cluster may provide new therapeutic opportunities for advanced MPM patients, depending on the nature of IL-18 gene expression.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

miR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma

et al. 2014

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“…These results indicate that vorinostat positively regulate synaptic plasticity genes expression and spine density in HIV infected neurons and may be useful as a therapeutic agent in the treatment of HAND. Zolinza (Merck, Whitehouse Station, NJ), a prescription drug contains vorinostat is currently being used for the treatment of cutaneous T-cell lymphoma [64], multiple myeloma [65], mesothelioma [66]. Therefore, further studies to use vorinostat as a therapeutic agent against HAND and in nicotine users need to be studied.…”

Section: Discussionmentioning

confidence: 99%

Vorinostat positively regulates synaptic plasticity genes expression and spine density in HIV infected neurons: role of nicotine in progression of HIV-associated neurocognitive disorder

et al. 2014

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BackgroundHIV-associated neurocognitive disorder (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occurs in approximately 50% of HIV infected individuals. In the United States, the prevalence of cigarette smoking ranges from 35-70% in HIV-infected individuals compared to 20% in general population. Cognitive impairment in heavy cigarette smokers has been well reported. However, the synergistic effects of nicotine and HIV infection and the underlying mechanisms in the development of HAND are unknown.ResultsIn this study, we explored the role of nicotine in the progression of HAND using SK-N-MC, a neuronal cell line. SK-N-MC cells were infected with HIV-1 in the presence or absence of nicotine for 7 days. We observed significant increase in HIV infectivity in SK-N-MC treated with nicotine compared to untreated HIV-infected neuronal cells. HIV and nicotine synergize to significantly dysregulate the expression of synaptic plasticity genes and spine density; with a concomitant increase of HDAC2 levels in SK-N-MC cells. In addition, inhibition of HDAC2 up-regulation with the use of vorinostat resulted in HIV latency breakdown and recovery of synaptic plasticity genes expression and spine density in nicotine/HIV alone and in co-treated SK-N-MC cells. Furthermore, increased eIF2 alpha phosphorylation, which negatively regulates eukaryotic translational process, was observed in HIV alone and in co-treatment with nicotine compared to untreated control and nicotine alone treated SK-N-MC cells.ConclusionsThese results suggest that nicotine and HIV synergize to negatively regulate the synaptic plasticity gene expression and spine density and this may contribute to the increased risk of HAND in HIV infected smokers. Apart from disrupting latency, vorinostat may be a useful therapeutic to inhibit the negative regulatory effects on synaptic plasticity in HIV infected nicotine abusers.

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“…We recently reported that HDAC inhibitors such as SAHA downregulate FLIP(S) and FLIP(L) expression in colorectal cancer 35 and MPM 36 cells in a proteasome-dependent manner. Thus, we assessed whether SAHA could sensitize MPM cells to SMC treatment.…”

Section: Resultsmentioning

confidence: 99%

SAHA overcomes FLIP-mediated inhibition of SMAC mimetic-induced apoptosis in mesothelioma

et al. 2013

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Malignant pleural mesothelioma (MPM) is a highly pro-inflammatory malignancy that is rapidly fatal and increasing in incidence. Cytokine signaling within the pro-inflammatory tumor microenvironment makes a critical contribution to the development of MPM and its resistance to conventional chemotherapy approaches. SMAC mimetic compounds (SMCs) are a promising class of anticancer drug that are dependent on tumor necrosis factor alpha (TNFα) signaling for their activity. As circulating TNFα expression is significantly elevated in MPM patients, we examined the sensitivity of MPM cell line models to SMCs. Surprisingly, all MPM cell lines assessed were highly resistant to SMCs either alone or when incubated in the presence of clinically relevant levels of TNFα. Further analyses revealed that MPM cells were sensitized to SMC-induced apoptosis by siRNA-mediated downregulation of the caspase 8 inhibitor FLIP, an antiapoptotic protein overexpressed in several cancer types including MPM. We have previously reported that FLIP expression is potently downregulated in MPM cells in response to the histone deacetylase inhibitor (HDACi) Vorinostat (SAHA). In this study, we demonstrate that SAHA sensitizes MPM cells to SMCs in a manner dependent on its ability to downregulate FLIP. Although treatment with SMC in the presence of TNFα promoted interaction between caspase 8 and the necrosis-promoting RIPK1, the cell death induced by combined treatment with SAHA and SMC was apoptotic and mediated by caspase 8. These results indicate that FLIP is a major inhibitor of SMC-mediated apoptosis in MPM, but that this inhibition can be overcome by the HDACi SAHA.

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Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent

Cited by 37 publications

References 48 publications

miR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma

miR-379/411 cluster regulates IL-18 and contributes to drug resistance in malignant pleural mesothelioma

Vorinostat positively regulates synaptic plasticity genes expression and spine density in HIV infected neurons: role of nicotine in progression of HIV-associated neurocognitive disorder

SAHA overcomes FLIP-mediated inhibition of SMAC mimetic-induced apoptosis in mesothelioma

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