Gomisin N enhances TNF-α-induced apoptosis via inhibition of the NF-κB and EGFR survival pathways

Waiwut, Pornthip; Shin, Myoung‐Sook; Inujima, Akiko; Zhou, Yue; Koizumi, Keiichi; Saiki, Ikuo; Sakurai, Hiroaki

doi:10.1007/s11010-010-0695-z

Cited by 18 publications

(14 citation statements)

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“…It was reported that gomisin N, a dibenzocyclooctadiene lignan similar to gomisin A, suppressed the NF-κB signaling pathway in HeLa cells. 8) These results suggest that inhibition of p-IκB and NF-κB reactions by gomisin A resulted in inhibition of the expression of pro-inflammatory mediators. It has been reported that gomisin A does not inhibit CCl(3) radical formation caused by CCl 4 induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 83%

“…Interestingly, a number of studies have shown that gomisin A has various pharmacological functions, including enhancement of tumor necrosis factor (TNF)-α-induced apoptosis, vascular relaxation, memory improvement, reduction of neuronal damage, and improvement of insulin sensitivity. [8][9][10][11][12] In addition, gomisin A showed a hepatoprotective effect in various animal models of hepatotoxicity including CCl 4 , acetaminophen and lipopolysaccharide (LPS) as well as promoting liver regeneration after partial hepatectomy. [13][14][15][16] However, the precise molecular mechanism of the hepatoprotective effects has not been comprehensively explored.…”

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confidence: 99%

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The Molecular Mechanisms of the Hepatoprotective Effect of Gomisin A against Oxidative Stress and Inflammatory Response in Rats with Carbon Tetrachloride-Induced Acute Liver Injury

Teraoka

Shimada

Aburada

2012

Biological & Pharmaceutical Bulletin

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Oxidative damage and inflammation are implicated in the pathogenesis of liver injury and fibrosis. In the present study, we investigated the molecular mechanism by which gomisin A conferred a hepatoprotective effect, focusing on its antioxidant and anti-inflammatory effects using rats with carbon tetrachloride (CCl 4 )-induced acute liver injury. Pretreatment with gomisin A prior to the administration of CCl 4 markedly prevented an increase in alanine aminotransferase, aspartate aminotransferase, and histological hepatic lesions. Gomisin A was also associated with a decrease in hepatic lipid peroxidation, and increased superoxide dismutase activity, suggesting that gomisin A has an antioxidant effect. In addition gomisin A treatment ameliorated mRNA levels of CCl 4 -induced inflammatory mediators, including tumor necrosis factor-α, interleukin-1β and inducible nitric oxide (NO) synthase, and the protein levels of transcriptional upregulator nuclear factor kappa B (NF-κB) and phospho-inhibitor of NF-κB (IκB). Furthermore, α-smooth muscle actin (α-SMA), a myofibroblast marker, was also inhibited by gomisin A treatment. These results suggest that gomisin A inhibits the oxidative stress and activation of NF-κB, leading to down-regulation of pro-inflammatory mediators and amelioration of fibrogenesis.Key words gomisin A; oxidative stress; inflammatory response; carbon tetrachloride; acute liver injuryThe liver has the important function of metabolizing and eliminating biological and xenobiotic compounds. Liver injury is considered to be a serious health problem leading to acute hepatitis, cholestasis, and cirrhosis. Hepatocellular injury usually leads to oxidative stress, inflammation, and activation of the innate immune system. These factors lead to the release of pro-inflammatory cytokines (that can result in hepatic necrosis) and of pro-fibrogenic cytokines that may cause increased synthesis of extracellular matrix components by activation of quiescent hepatic stellate cells (HSCs).

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Section: Discussionmentioning

confidence: 83%

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confidence: 99%

The Molecular Mechanisms of the Hepatoprotective Effect of Gomisin A against Oxidative Stress and Inflammatory Response in Rats with Carbon Tetrachloride-Induced Acute Liver Injury

Teraoka

Shimada

Aburada

2012

Biological & Pharmaceutical Bulletin

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“…Trimerization of the death domain leads to the recruitment of an adaptor molecule, FADD, and subsequent activation of caspase-8 and caspase-10, which in turn leads to the cleavage of caspase-3 and death substrates (9,11,12). Previous studies indicated that TNF-α induced cell death through caspase-3 activation and PARP cleavage (36,37). It has been reported that caspase-8 activation was observed in the TRAIL-induced apoptosis of HeLa cancer cells (11,31).…”

Section: Discussionmentioning

confidence: 99%

“…In the death receptor pathway, nuclear factor-κB (NF-κB), a well-known transcription factor, protects cells from apoptosis by the activation of survival factors such as anti-apoptotic proteins (43). It has been shown in HeLa cells that the inhibition of NF-κB can sensitize the cancer cells to TNF-α-and TRAIL-induced apoptosis (29,31,37). The present results showed that the ethanolic extract of T. peruviana flowers had no effect on TNF-α-induced NF-κB activation (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Ethanolic extract of Thevetia peruviana flowers enhances TNF-α and TRAIL-induced apoptosis of human cervical cancer cells via intrinsic and extrinsic pathways

2017

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Abstract. Tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are promising candidates for cancer treatment due to their ability to induce apoptosis through death receptor stimulation. However, their usage may be limited due to the resistance of cancer cells to TNF-α-and TRAIL-induced apoptosis. Currently, there is interest in screening for natural products that can sensitize cancer cells to TNF-α-and TRAIL-induced apoptosis for their use in combination with TNF-α or TRAIL. It was previously reported that the bark extract of Thevetia peruviana showed a reversal effect on TRAIL-resistance in human gastric adenocarcinoma cell lines. In the present study, the effects of the ethanolic extract of T. peruviana flowers on TNF-α-and TRAIL-induced apoptosis of human cervical cancer HeLa cells were investigated in vitro by determining cell viability and apoptosis using a WST-1 cell proliferation assay and immunoblot analysis, respectively. The ethanolic extract of T. peruviana flowers promoted TNF-α and TRAIL-mediated cell death through the activation of the caspase cascade, poly(ADP-ribose) polymerase and BH3-interacting domain death agonist cleavage. Combined treatment using the extract plus TNF-α resulted in downregulation of anti-apoptotic protein, including myeloid cell leukemia sequence-1, B-cell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis protein and survivin, while the combined treatment with TRAIL downregulated Bcl-XL. Thus, the ethanolic extract of T. peruviana flowers has potential in sensitizing the TNF-α-and TRAIL-induced apoptosis of HeLa cells via the intrinsic and extrinsic pathways. IntroductionChemotherapy is one of the major standard treatments that is beneficial for numerous cancer types due to its efficient induction of tumor cell death by apoptosis. At present, the cancer resistance of chemotherapeutic drugs is a major drawback that leads to the failure of cancer treatments. Chemotherapeutic drugs eliminate tumor cells by the induction of apoptosis via two distinct pathways, which act through the mitochondria (intrinsic signaling pathway) or through death receptors on the cell surface (extrinsic signaling pathway) (1). Induction of apoptosis via the intrinsic signaling pathway is initiated by severe cell stress, including DNA damage, mitotic catastrophe, hypoxia and cell cycle checkpoint defects. The majority of conventional chemotherapeutic drugs trigger DNA damage and induce apoptosis via the intrinsic signaling pathway by the activation of tumor suppressor protein, p53, which leads to the breakdown of mitochondrial membrane and the release of cytochrome c into the cytosol. Cytochrome c binds to the adaptor apoptotic protease activating factor 1, forming an apoptosome. The apoptosome subsequently activates caspase-9 and caspase-3, which results in the cleavage of death substrates (2-4). Defects in intrinsic apoptosis signal transduction, such as the mutation of p53, contributes to the chemotherapeutic drug resistance of cancer (5,6). The extrinsic pa...

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“…32,33) We previous demonstrated that gomisin N, but not gomisin A, inhibited the TNF-α-induced NF-κB and epidermal growth factor receptor (EGFR) signaling pathways in HeLa cells, which resulted in enhanced pro-apoptotic events. 34) However gomisin A also inhibited cell proliferation; therefore, in this study, we investigated the molecular mechanisms of the antiproliferative effect of gomisin A in TNF-α-treated HeLa cells.…”

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confidence: 99%

Gomisin A Enhances Tumor Necrosis Factor-α-Induced G1 Cell Cycle Arrest <i>via</i> Signal Transducer and Activator of Transcription 1-Mediated Phosphorylation of Retinoblastoma Protein

Waiwut

Shin

Yokoyama

et al. 2012

Biological & Pharmaceutical Bulletin

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Gomisin A, a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra chinensis, has been reported as an anti-cancer substance. In this study, we investigated the effects of gomisin A on cancer cell proliferation and cell cycle arrest in HeLa cells. Gomisin A significantly inhibited cell proliferation in a dose-dependent manner after 72 h treatment, especially in the presence of tumor necrosis factor-α (TNF-α), due to cell cycle arrest in the G1 phase with the downregulation of cyclin D1 expression and Retinoblastoma (RB) phosphorylation. In addition, gomisin A in combination with TNF-α strongly suppressed the expression of signal transducer and activator of transcription 1 (STAT1). Inhibition of STAT1 pathways by a small-interfering RNA against STAT1 and AG490 Janus kinase (JAK) kinase inhibitor AG490 reduced the cyclin D1 expression and RB phosphorylation, indicating that JAK-mediated STAT1 activation is involved in gomisin A-induced G1 cell cycle arrest.Key words gomisin A; tumor necrosis factor-α; cell cycle; cyclin D1; Retinoblastoma Cancer cells often have a selective growth advantage due to deregulation of cell cycle proteins, causing aberrant growth signaling that drives tumor development.1-4) The eukaryotic cell cycle is regulated through the sequential activation and inactivation of cyclin-dependent kinases (CDKs). Deregulation of G1 to S-phase transition is implicated in the pathogenesis of most human cancers. 5) Retinoblastoma protein (RB) is a critical target protein in G1-S checkpoint control. Phosphorylation of RB by CDK/cyclin complex results in the release of active E2F transcription factor to stimulate the transcription of genes involved in DNA synthesis and S-phase progression. 6,7)Cyclin D1 can accelerate the progress of cells through the G1 phase by binding to CDKs and subsequently phosphorylating RB. Overexpression of cyclin D1 has been shown to shorten the G1 phase in cancer cells and is most frequently associated with human cancer. 8,9) Cyclin D1 is rarely mutated, but its overexpression confers a selective growth advantage and hence acts as a driver of neoplastic growth in various cancers. 10,11)The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway plays a significant role in various physiological processes, including immune function, cell growth, differentiation, and hematopoiesis. 12) Constitutive activation of STAT3 correlates with cell proliferation in breast carcinoma 13) and non small-cell lung cancer.14) It has been revealed that inhibition of JAK-STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells.15) Activated STAT3 correlates with elevated cyclin D1 protein in primary breast tumors and breast cancer-derived cell lines.16) Our recent study demonstrated that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis was enhanced by STAT1 knockdown.17) Consequently, regulation of STATs can be considered as a key major target in controlling the gr...

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Gomisin N enhances TNF-α-induced apoptosis via inhibition of the NF-κB and EGFR survival pathways

Cited by 18 publications

References 23 publications

The Molecular Mechanisms of the Hepatoprotective Effect of Gomisin A against Oxidative Stress and Inflammatory Response in Rats with Carbon Tetrachloride-Induced Acute Liver Injury

The Molecular Mechanisms of the Hepatoprotective Effect of Gomisin A against Oxidative Stress and Inflammatory Response in Rats with Carbon Tetrachloride-Induced Acute Liver Injury

Ethanolic extract of Thevetia peruviana flowers enhances TNF-α and TRAIL-induced apoptosis of human cervical cancer cells via intrinsic and extrinsic pathways

Gomisin A Enhances Tumor Necrosis Factor-α-Induced G1 Cell Cycle Arrest <i>via</i> Signal Transducer and Activator of Transcription 1-Mediated Phosphorylation of Retinoblastoma Protein

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