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Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation.

Luan Z, He Y, He F, Chen Z - Mol Med Rep (2014)

Bottom Line: Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated.Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation.Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

ABSTRACT
The enhancement of apoptosis is a therapeutic strategy used in the treatment of cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, hepatocellular carcinoma (HCC) cells exhibit marked resistance to the induction of cell death by TRAIL. The present study investigated whether rocaglamide, a naturally occurring product isolated from the genus Aglaia, is able to sensitize resistant HCC cells to TRAIL-mediated apoptosis. Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated. The in vivo efficacy of rocaglamide was determined in TRAIL-resistant Huh-7-derived tumor xenografts. Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation. Furthermore, rocaglamide markedly inhibited tumor growth from Huh-7 cells propagated in severe combined immunodeficient mice, suggesting that chemosentization also occurred in vivo. These data suggest that rocaglamide acted synergistically with TRAIL against the TRAIL-resistant HCC cells. Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC.

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Related in: MedlinePlus

RocA downregulates c-FLIP. (A and B) HepG2 and Huh-7 cells were treated with RocA (100 nM) for 12 h. The cell lysates were analyzed using western blot analysis with the antibodies indicated. The control is represented by cells treated with DMSO only. Results are representative of three independent experiments. RocA, rocaglamide; DMSO, dimethyl sulfoxide; c-FLIP, cellular FLICE-like inhibitory protein; DR, death receptor.
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f3-mmr-11-01-0203: RocA downregulates c-FLIP. (A and B) HepG2 and Huh-7 cells were treated with RocA (100 nM) for 12 h. The cell lysates were analyzed using western blot analysis with the antibodies indicated. The control is represented by cells treated with DMSO only. Results are representative of three independent experiments. RocA, rocaglamide; DMSO, dimethyl sulfoxide; c-FLIP, cellular FLICE-like inhibitory protein; DR, death receptor.

Mentions: c-FLIP, which is highly homologous to caspase-8 but is catalytically inactive, is able to bind to caspase-8 and the FADD and inhibit TRAIL-induced apoptosis, thus disrupting the death-inducing signaling complex (DISC) (22). Notably, HCC tumors exhibit high resistance to TRAIL due to the overexpression of c-FLIP (23). Following the observation that rocaglamide is able to overcome TRAIL-resistance in the HCC cells and activate caspase-8, the present study investigated whether this effect correlated with c-FLIP. Therefore, the effect of rocaglamide on the levels of c-FLIP, which is highly expressed in HCC cells, was examined (Fig. 3A). Notably, the resulting data also suggest that rocaglamide treatment resulted in downregulation of the c-FLIP protein in the HepG2 and Huh-7 cells (Fig. 3A). The resulting effect of rocaglamide on the levels of c-FLIP was consistent with the effects of rocaglamide on caspase-dependent apoptosis.


Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation.

Luan Z, He Y, He F, Chen Z - Mol Med Rep (2014)

RocA downregulates c-FLIP. (A and B) HepG2 and Huh-7 cells were treated with RocA (100 nM) for 12 h. The cell lysates were analyzed using western blot analysis with the antibodies indicated. The control is represented by cells treated with DMSO only. Results are representative of three independent experiments. RocA, rocaglamide; DMSO, dimethyl sulfoxide; c-FLIP, cellular FLICE-like inhibitory protein; DR, death receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4237083&req=5

f3-mmr-11-01-0203: RocA downregulates c-FLIP. (A and B) HepG2 and Huh-7 cells were treated with RocA (100 nM) for 12 h. The cell lysates were analyzed using western blot analysis with the antibodies indicated. The control is represented by cells treated with DMSO only. Results are representative of three independent experiments. RocA, rocaglamide; DMSO, dimethyl sulfoxide; c-FLIP, cellular FLICE-like inhibitory protein; DR, death receptor.
Mentions: c-FLIP, which is highly homologous to caspase-8 but is catalytically inactive, is able to bind to caspase-8 and the FADD and inhibit TRAIL-induced apoptosis, thus disrupting the death-inducing signaling complex (DISC) (22). Notably, HCC tumors exhibit high resistance to TRAIL due to the overexpression of c-FLIP (23). Following the observation that rocaglamide is able to overcome TRAIL-resistance in the HCC cells and activate caspase-8, the present study investigated whether this effect correlated with c-FLIP. Therefore, the effect of rocaglamide on the levels of c-FLIP, which is highly expressed in HCC cells, was examined (Fig. 3A). Notably, the resulting data also suggest that rocaglamide treatment resulted in downregulation of the c-FLIP protein in the HepG2 and Huh-7 cells (Fig. 3A). The resulting effect of rocaglamide on the levels of c-FLIP was consistent with the effects of rocaglamide on caspase-dependent apoptosis.

Bottom Line: Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated.Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation.Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

ABSTRACT
The enhancement of apoptosis is a therapeutic strategy used in the treatment of cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, hepatocellular carcinoma (HCC) cells exhibit marked resistance to the induction of cell death by TRAIL. The present study investigated whether rocaglamide, a naturally occurring product isolated from the genus Aglaia, is able to sensitize resistant HCC cells to TRAIL-mediated apoptosis. Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated. The in vivo efficacy of rocaglamide was determined in TRAIL-resistant Huh-7-derived tumor xenografts. Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation. Furthermore, rocaglamide markedly inhibited tumor growth from Huh-7 cells propagated in severe combined immunodeficient mice, suggesting that chemosentization also occurred in vivo. These data suggest that rocaglamide acted synergistically with TRAIL against the TRAIL-resistant HCC cells. Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC.

Show MeSH
Related in: MedlinePlus