The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation

Carlisi, Daniela; Lauricella, Marianna; D’Anneo, Antonella; Emanuele, Sonia; Angileri, Liliana; Fazio, Pietro Di; Santulli, Andrea; Vento, Renza; Tesoriere, Giovanni

doi:10.1016/j.ejca.2009.06.024

Cited by 71 publications

(58 citation statements)

References 44 publications

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“…At least, two papers already reported same finding. Carlisi et al 12 reported that the addition of vorinostat to TRAIL induced remarkable decrease in both p65 and p50 NF-kB binding activity of hepatoma cells, which was enhanced by TRAIL alone. They suggested that activated caspase-3 cleaved both p65 and p50 subunit of NF-kB, because the pan-caspase inhibitor z-VAD completely abolish this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…Vorinostat induces the increased expression of death receptor 5 11 and the decreased expression of c-FLIP, and finally provoked the rapid production of TRAIL-DISC formation and activation of the caspase system. 12 Real time-PCR for DR5 mRNA revealed that enhanced DR5 expression by vorinostat is due to increased DR5 mRNA transcription. Combined treatment of vorinostat and TRAIL enhanced the therapeutic effect on a TRAIL-resistant breast cancer model.…”

Section: Discussionmentioning

confidence: 99%

“…Increased DR5 expression by vorinostat was suggested as the mechanism of sensitization. 11 Recently, Carlisi et al 12 showed that vorinostat sensitizes hepatocellular carcinoma cells to TRAIL by increasing DR5 expression and decreasing c-FLIP. Also, sequential treatment of vorinostat followed by TRAIL is more effective in growth suppression of tumor formed by TRAIL-resistant breast cancer cells in BALB/c nude mice.…”

Section: Introductionmentioning

confidence: 99%

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Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

Park

et al. 2011

Cancer Gene Ther

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Soluble TRAIL and adenovirus (ad)-TRAIL exhibit a strong antitumor effect by inducing apoptosis. Vorinostat is the histone deacetylase (HDAC) inhibitor that induces cell death in cancer cell lines and regulates the expression of epigenetically silenced genes, such as Coxackie adenoviral receptor (CAR), the receptor for adenoviral entry. We propose a new strategy in which vorinostat will induce high expression of ad-TRAIL and a strong antitumor response, and investigated the mechanism involved. The effect of vorinostat on transcription and expression of TRAIL from ad-TRAIL-transduced lung cancer cells were confirmed by reverse transciption-PCR (RT-PCR), quantitative real time-PCR and western blot assay. Anti-tumor effects were measured after cotreatment of vorinostat and ad-TRAIL, and the drug interactions were analyzed. After combined treatment of vorinostat and ad-TRAIL, apoptosis and western blot assays for Akt, Bcl-2 and caspase were performed. Vorinostat increased the expression of CAR in lung cancer cell lines and increased the expression of luciferase (luc) from ad-luc-transduced cells and TRAIL from ad-TRAIL-transduced cells. RT-PCR and quantitative real time-PCR, after sequential vorinostat treatment, revealed that vorinostat may enhance TRAIL expression from ad-TRAIL by increasing transduction through enhanced CAR expression and increasing adenoviral transgene transcription. Combined vorinostat and ad-TRAIL treatment showed the synergistic anti-tumor effect in lung cancer cell lines. Combined vorinostat and ad-TRAIL induced stronger apoptosis induction, suppression of NF-kB activation and breakdown of the anti-apoptotic molecule Bcl-2. In conclusion, the vorinostat synergistically enhanced the anti-tumor effect of ad-TRAIL by (1) increasing adenoviral transduction through the increased expression of CAR and (2) increasing adenoviral transgene (TRAIL) transcription in lung cancer cell lines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

Park

et al. 2011

Cancer Gene Ther

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“…Sensitization of cancer cells to TRAIL-induced apoptosis can result either by the increase in the level of TRAIL receptors or by the decrease in the level of anti-apoptotic factors such as c-FLIP or IAPs [20,27]. Therefore, we performed western blotting experiments to evaluate the effects of the drugs on both TRAIL receptors and c-FLIP.…”

Section: The Effects Of Saha and Trail On The Expression Of Death Recmentioning

confidence: 99%

“…Our previous studies demonstrated the ability of suberoylanilide hydroxamic acid (SAHA), an inhibitor of HDAC, to sensitize human hepatocarcinoma cells to TRAIL-induced apoptosis by enhancing the expression of DR5 and decreasing the level of the anti-apoptotic factor c-FLIP [20].…”

Section: Introductionmentioning

confidence: 99%

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

et al. 2012

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a b s t r a c t SAHA, an inhibitor of histone deacetylase activity, has been shown to sensitize tumor cells to apoptosis induced by TRAIL, a member of TNF-family. In this paper we investigated the effect of SAHA/TRAIL combination in two breast cancer cell lines, the ERaÀpositive MCF-7 and the ERaÀnegative MDA-MB231. Treatment of MDA-MB231 and MCF-7 cells with SAHA in combination with TRAIL caused detachment of cells followed by anoikis, a form of apoptosis which occurs after cell detachment, while treatment with SAHA or TRAIL alone did not produce these effects. The effects were more evident in MDA-MB231 cells, which were chosen for ascertaining the mechanism of SAHA/TRAIL action. Our results show that SAHA decreased the level of c-FLIP, thus favouring the interaction of TRAIL with the specific death receptors DR4 and DR5 and the consequent activation of caspase-8. These effects increased when the cells were treated with SAHA/TRAIL combination. Because z-IEDT-fmk, an inhibitor of caspase-8, prevented both the cleavage of the focal adhesion-kinase FAK and cell detachment, we suggest that activation of caspase-8 can be responsible for both the decrement of FAK and the consequent cell detachment. In addition, treatment with SAHA/TRAIL combination caused dissipation of DJ m , activation of caspase-3 and decrement of both phospho-EGFR and phospho-ERK1/2, a kinase which is involved in the phosphorylation of BimEL. Therefore, co-treatment also induced decrement of phospho-BimEL and a concomitant increase in the dephosphorylated form of BimEL, which plays an important role in the induction of anoikis.Our findings suggest the potential application of SAHA in combination with TRAIL in clinical trials for breast cancer.

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shRNA‐mediated silencing of Gli2 gene inhibits proliferation and sensitizes human hepatocellular carcinoma cells towards TRAIL‐induced apoptosis

Zhang

Liu

Wang

et al. 2011

J of Cellular Biochemistry

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Aberrant activation of the Hedgehog (Hh) signaling pathway has been reported in various cancer types including hepatocellular carcinoma (HCC). As a key effector of this signaling, Gli2 plays a crucial role in carcinogenesis, including the activation of genes encoding apoptosis inhibitors and cell-cycle regulators. In this study, we examined the role of Gli2 proliferation and survival of HCC cells. First, the expression levels of Hh pathway components were detected in a subset of HCC cell lines. To establish the role of Gli2 in maintaining the tumorigenic properties of HCC cells, we developed small hairpin RNA (shRNA) targeting Gli2 and transfected it into SMMC-7721 cell, which was selected with high level of Hh signaling expression. Next, effects of Gli2 gene silencing, on cell proliferation and on the expression of cell cycle-related proteins were evaluated, then, whether down-regulation of Gli2 renders HCC cell susceptible to TRAIL was examined in vitro. Knockdown of Gli2 inhibited cell proliferation and induced G1 phase arrest of cell cycle in SMMC-7721 cell through down-regulation of cyclin D1, cyclinE2, and up-regulation of p21-WAF1. Also, Gli2 gene siliencing sensitized SMMC-7721 cell to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by reducing the expression of the long and short isoform of c-FLIP and Bcl-2, and then augmented the activation of initiator caspases-8/-9 and effector caspases-3, which induces PARP cleavage. In conclusion, our data suggest that Gli2 plays a predominant role in the proliferation and apoptosis resistance of HCC cells, and that knockdown of Gli2 may be a novel anticancer strategy for the treatment of HCC.

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The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation

Cited by 71 publications

References 44 publications

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

shRNA‐mediated silencing of Gli2 gene inhibits proliferation and sensitizes human hepatocellular carcinoma cells towards TRAIL‐induced apoptosis

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