Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP Pathway
Sinulariolide, an active compound isolated from the cultured soft coral Sinularia flexibilis, has potent anti-microbial and anti-tumorigenesis effects towards melanoma and bladder cancer cells. In this study, we investigated the effects of sinulariolide on hepatocellular carcinoma (HCC) cell growth...
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| Format: | Article |
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MDPI AG
2013-08-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/18/9/10146 |
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| author | Yu-Jen Wu Shun-Hsiang Weng Han Hisang Huang Feng-Jen Tsai Zih-Yan Yang Ming-Hui Liao Chun-Tzu Hung Jen-Jie Lin Hsiang-Hao Chao Chia-Yu Tsao Yi-Jen Chen Jui-Hsin Su |
| author_facet | Yu-Jen Wu Shun-Hsiang Weng Han Hisang Huang Feng-Jen Tsai Zih-Yan Yang Ming-Hui Liao Chun-Tzu Hung Jen-Jie Lin Hsiang-Hao Chao Chia-Yu Tsao Yi-Jen Chen Jui-Hsin Su |
| author_sort | Yu-Jen Wu |
| collection | DOAJ |
| description | Sinulariolide, an active compound isolated from the cultured soft coral Sinularia flexibilis, has potent anti-microbial and anti-tumorigenesis effects towards melanoma and bladder cancer cells. In this study, we investigated the effects of sinulariolide on hepatocellular carcinoma (HCC) cell growth and protein expression. Sinulariolide suppressed the proliferation and colony formation of HCC HA22T cells in a dose-dependent manner and induced both early and late apoptosis according to flow cytometry, Annexin V/PI stain and TUNEL/DAPI stain analyses. A mechanistic analysis demonstrated that sinulariolide-induced apoptosis was activated through a mitochondria-related pathway, showing up-regulation of Bax, Bad and AIF, and down- regulation of Bcl-2, Bcl-xL, MCl-1 and p-Bad. Sinulariolide treatment led to loss of the mitochondrial membrane potential, release of mitochondrial cytochrome c to the cytosol, and activation of both caspase-9 and caspase-3. Sinulariolide-induced apoptosis was significantly blocked by the caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK. The increased expression of cleaved PARP also suggested that caspase-independent apoptotic pathway was involved. In the western blotting; the elevation of ER chaperones GRP78; GRP94; and CALR; as well as up-regulations of PERK/eIF2α/ATF4/CHOP; and diminished cell death with pre-treatment of eIF2α phosphatase inhibitor; salubrinal; implicated the involvement of ER stress-mediated PERK/eIF2α/ATF4/CHOP apoptotic pathway following sinulariolide treatment in hepatoma cells. The current study suggested sinulariolide-induced hepatoma cell cytotoxicity involved multiple apoptotic signal pathways. This may implicate that sinulariolide is a potential compound for the treatment of hepatocellular carcinoma. |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-14T14:41:02Z |
| publishDate | 2013-08-01 |
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| spelling | doaj.art-d5b00270e4744e7790287a6cfc7235f82022-12-21T22:57:25ZengMDPI AGMolecules1420-30492013-08-01189101461016110.3390/molecules180910146Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP PathwayYu-Jen WuShun-Hsiang WengHan Hisang HuangFeng-Jen TsaiZih-Yan YangMing-Hui LiaoChun-Tzu HungJen-Jie LinHsiang-Hao ChaoChia-Yu TsaoYi-Jen ChenJui-Hsin SuSinulariolide, an active compound isolated from the cultured soft coral Sinularia flexibilis, has potent anti-microbial and anti-tumorigenesis effects towards melanoma and bladder cancer cells. In this study, we investigated the effects of sinulariolide on hepatocellular carcinoma (HCC) cell growth and protein expression. Sinulariolide suppressed the proliferation and colony formation of HCC HA22T cells in a dose-dependent manner and induced both early and late apoptosis according to flow cytometry, Annexin V/PI stain and TUNEL/DAPI stain analyses. A mechanistic analysis demonstrated that sinulariolide-induced apoptosis was activated through a mitochondria-related pathway, showing up-regulation of Bax, Bad and AIF, and down- regulation of Bcl-2, Bcl-xL, MCl-1 and p-Bad. Sinulariolide treatment led to loss of the mitochondrial membrane potential, release of mitochondrial cytochrome c to the cytosol, and activation of both caspase-9 and caspase-3. Sinulariolide-induced apoptosis was significantly blocked by the caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK. The increased expression of cleaved PARP also suggested that caspase-independent apoptotic pathway was involved. In the western blotting; the elevation of ER chaperones GRP78; GRP94; and CALR; as well as up-regulations of PERK/eIF2α/ATF4/CHOP; and diminished cell death with pre-treatment of eIF2α phosphatase inhibitor; salubrinal; implicated the involvement of ER stress-mediated PERK/eIF2α/ATF4/CHOP apoptotic pathway following sinulariolide treatment in hepatoma cells. The current study suggested sinulariolide-induced hepatoma cell cytotoxicity involved multiple apoptotic signal pathways. This may implicate that sinulariolide is a potential compound for the treatment of hepatocellular carcinoma.http://www.mdpi.com/1420-3049/18/9/10146hepatocellular carcinomasinulariolidemitochondrialPERK/eIF2α/ATF4/CHOPapoptosis |
| spellingShingle | Yu-Jen Wu Shun-Hsiang Weng Han Hisang Huang Feng-Jen Tsai Zih-Yan Yang Ming-Hui Liao Chun-Tzu Hung Jen-Jie Lin Hsiang-Hao Chao Chia-Yu Tsao Yi-Jen Chen Jui-Hsin Su Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP Pathway Molecules hepatocellular carcinoma sinulariolide mitochondrial PERK/eIF2α/ATF4/CHOP apoptosis |
| title | Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP Pathway |
| title_full | Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP Pathway |
| title_fullStr | Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP Pathway |
| title_full_unstemmed | Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP Pathway |
| title_short | Sinulariolide Induced Hepatocellular Carcinoma Apoptosis through Activation of Mitochondrial-Related Apoptotic and PERK/eIF2α/ATF4/CHOP Pathway |
| title_sort | sinulariolide induced hepatocellular carcinoma apoptosis through activation of mitochondrial related apoptotic and perk eif2α atf4 chop pathway |
| topic | hepatocellular carcinoma sinulariolide mitochondrial PERK/eIF2α/ATF4/CHOP apoptosis |
| url | http://www.mdpi.com/1420-3049/18/9/10146 |
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