• Journal of Applied Biological Chemistry
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• v.66
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• pp.138-143
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• 2023

Liver fibrosis is caused by metabolic problems such as cholestasis, genetic problems, or viral infections. Inhibiting hepatic stellate cell (HSC) activation or inducing selective apoptosis of activated HSCs is used as a treatment strategy for liver fibrosis. It has been reported that when HSCs are activated, their apoptosis sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is enhanced because the expression of death receptor 5 is elevated. Finding a natural compound that can enhance the apoptotic effect of TRAIL on HSCs is a necessary strategy for liver fibrosis treatment. It was confirmed here that mangosteen-derived gartanin increased the effect of TRAIL-induced apoptosis by increasing the expression of DR5 in a p38-dependent manner in the hepatic stellate cell line LX-2. Combined treatment with gartanin and TRAIL accelerated DNA cleavage through caspase-3 activation and enhanced antifibrotic effects in LX-2 cells.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.6991-6996
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• 2015

In the past decade, the incidence and mortality rates of cholangiocarcinoma (CCA) have been increasing worldwide. The relatively low responsiveness of CCA to conventional chemotherapy leads to poor overall survival. Recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) has emerged as the most promising anti-cancer therapeutic agent since it is able to selectively induce apoptosis of tumor cells but not normal cells. In this study, we aimed to investigate the therapeutic effect of TRAIL in CCA cell lines (M213, M214 and KKU100) compared with the immortal biliary cell line, MMNK1, either alone or in combination with a subtoxic dose of 5-fluorouracil (5-FU). We found that recombinant human TRAIL (rhTRAIL) was a potential agent which significantly inhibited cell proliferation and mediated caspase activities (caspases 8, 9 and 3/7) and apoptosis of CCA cells. The combined treatment of rhTRAIL and 5-FU effectively enhanced inhibition of CCA cell growth with a smaller effect on MMNK1. Our finding suggests TRAIL to be a novel anti-cancer therapeutic agent and advantage of its combination with a conventional chemotherapeutic drug for effective treatment of CCA.

• BMB Reports
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• v.52 no.2
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• pp.119-126
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• 2019

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) initiates the extrinsic apoptotic pathway through formation of the death-inducing signaling complex (DISC), followed by activation of effector caspases. TRAIL receptors are composed of death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and osteoprotegerin. Among them, only DRs activate apoptotic signaling by TRAIL. Since the levels of DR expressions are higher in cancer cells than in normal cells, TRAIL selectively activates apoptotic signaling pathway in cancer cells. However, multiple mechanisms, including down-regulation of DR expression and pro-apoptotic proteins, and up-regulation of anti-apoptotic proteins, make cancer cells TRAIL-resistant. Therefore, many researchers have investigated strategies to overcome TRAIL resistance. In this review, we focus on protein regulation in relation to extrinsic apoptotic signaling pathways via ubiquitination. The ubiquitin proteasome system (UPS) is an important process in control of protein degradation and stabilization, and regulates proliferation and apoptosis in cancer cells. The level of ubiquitination of proteins is determined by the balance of E3 ubiquitin ligases and deubiquitinases (DUBs), which determine protein stability. Regulation of the UPS may be an attractive target for enhancement of TRAIL-induced apoptosis. Our review provides insight to increasing sensitivity to TRAIL-mediated apoptosis through control of post-translational protein expression.

• Journal of Life Science
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• v.21 no.11
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• pp.1549-1557
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• 2011

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in many types of transformed cells; however, some human hepatocellular carcinoma cells are particularly resistant to the effects of TRAIL. Although genistein, a natural isoflavonoid phytoestrogen, has been shown to have pro-apoptotic activity against human cancer cell lines, little is known about the mechanism of genistein in terms of TRAIL-induced apoptosis. In the present study, it was investigated whether or not combined treatment with genistein and TRAIL synergistically induced apoptosis in Hep3B hepatocarcinoma cells. Results indicate that treatment with TRAIL in combination with nontoxic concentrations of genistein sensitized TRAIL-resistant Hep3B cells to TRAIL-induced apoptosis, which was associated with mitochondrial dysfunction. Further, the inhibition of p38 mitogen-activated protein kinase (MAPK) activation markedly decreased genistein and TRAIL-induced cell viability and apoptosis by enhanced truncation of Bid, increase of pro-apoptotic Bax, decrease of anti-apoptotic Bcl-2, and release of cytochrome c from mitochondria to cytoplasm. Activation of caspases and degradation of poly (ADP-ribose) polymerase induced by the combined treatment was also markedly increased by the inhibition of p38 MAPK, through the mitochondrial amplification step. In conclusion, our data suggest that genistein sensitizes TRAIL-induced-apoptosis via p38 MAPK-dependent pathway.

• Journal of Pharmaceutical Investigation
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• v.33 no.4
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• pp.261-265
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• 2003

Tumor necrosis facto-related apoptosis-inducing ligand (TRAIL) is a recently identified member of the tumor necrosis factor cytokine superfamily. TRAIL has been shown to induce apoptosis in a number of tumor cells whereas cells from most of normal tissues are highly resistant to TRAIL-induced apoptosis. These observations have raised considerable interest in the use of TRAIL in tumor therapy. In this study we report the biodistribution fates and serum expression pattern of plasmid DNA encoding TRAIL (pTRAIL) delivered in erythrocyte ghosts (EG). pTRAIL was loaded into EG by electroportion in a hypotonic medium The mRNA expression of pTRAIL was prolonged following delivery in EG-encapsulated forms. EG containing pTRAIL showed significant levels of mRNA expression in the blood over 9 days. The organ expression patterns of pTRAIL delivered via EG, however, did not significantly differ from those of naked pTRAIL, indicating that the expression-enhancing effect of EG containing pTRAIL was localized to the blood. These results suggest that pTRAIL-loaded EG might be of potential use in the treatment of hematological diseases such as TRAIL-sensitive leukemia.

• Journal of the Korean Society of Food Science and Nutrition
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• v.40 no.9
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• pp.1201-1207
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• 2011

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a potent tool to trigger apoptosis in cancer therapy. However, as many types of cancer cells remain resistant towards TRAIL-induced cytotoxicity, several combined therapy approaches aimed to sensitize cells to TRAIL have been developed. Genistein, a natural isoflavonoid phytoestrogen, has been shown to have anticancer activity by inducing cell cycle arrest at G2M phase as well as apoptosis in various cancer cell lines. In the present study, we showed that treatment with TRAIL in combination with subtoxic concentrations of genistein sensitized U937 human leukemia cells to TRAIL-mediated apoptosis. Combined treatment with genistein and TRAIL effectively activated caspases through Bid truncation (tBid) and down-regulation of cellular caspase-8 (FLICE)-like inhibitory proteinL ($cFLIP_L$). However, the apoptotic effects of co-treatment with genistein and TRAIL were significantly inhibited by specific caspase inhibitors, which demonstrates the important role of caspases in apoptosis induced by genistein and TRAIL. Overall, our results indicate that genistein can potentiate TRAIL-induced apoptosis through down-regulation of $cFLIP_L$ and up-regulation of pro-apoptotic tBid proteins.

• Biomolecules & Therapeutics
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• v.23 no.1
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• pp.31-38
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• 2015

Histone acetylation plays a critical role in the regulation of transcription by altering the structure of chromatin, and it may influence the resistance of some tumor cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) by regulating the gene expression of components of the TRAIL signaling pathway. In this study, we investigated the effects and molecular mechanisms of trichostatin A (TSA), a histone deacetylase inhibitor, in sensitizing TRAIL-induced apoptosis in Caki human renal carcinoma cells. Our results indicate that nontoxic concentrations of TSA substantially enhance TRAIL-induced apoptosis compared with treatment with either agent alone. Cotreatment with TSA and TRAIL effectively induced cleavage of Bid and loss of mitochondrial membrane potential (MMP), which was associated with the activation of caspases (-3, -8, and -9) and degradation of poly (ADP-ribose) polymerase (PARP), contributing toward the sensitization to TRAIL. Combined treatment with TSA and TRAIL significantly reduced the levels of the cellular Fas-associated death domain (FADD)-like interleukin-$1{\beta}$-converting enzyme (FLICE) inhibitory protein (c-FLIP), whereas those of death receptor (DR) 4, DR5, and FADD remained unchanged. The synergistic effect of TAS and TRAIL was perfectly attenuated in c-$FLIP_L$-overexpressing Caki cells. Taken together, the present study demonstrates that down-regulation of c-FLIP contributes to TSA-facilitated TRAIL-induced apoptosis, amplifying the death receptor, as well as mitochondria-mediated apoptotic signaling pathways.

• Journal of Life Science
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• v.18 no.1
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• pp.120-128
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• 2008

The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/ Apo1L is a cytokine that activates apoptosis through cell surface death receptors. TRAIL has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. Euphorbiae humifusae Wind has been used in traditional Oriental medicine as a folk remedy used for the treatment of cancer. However, the mechanism responsible for the anticancer effects of E. humifusae not clearly understood. Here, we show that treatment with subtoxic doses of water extract of E. humifusae (WEEH) in combination with TRAIL induces apoptosis in TRAIL-resistant human gastric carcinoma AGS cells. Combined treatment with WEEH and TRAIL induced chromatin condensation and sub-G1 phase DNA content. These indicators of apoptosis were correlated with the induction of caspase activity that resulted in the cleavage of poly (ADP-ribose) polymerase. Combined treatment also triggered the loss of mitochondrial membrane potential. Furthermore, co-treatment with WEEH and TRAIL down-regulated the protein levels of the anti-apoptotic proteins such as Bcl-2, Bcl-xL, XIAP and cIAP-1. Although more study will be needed to examine the detailed mechanisms, this combined treatment may offer an attractive strategy for safely treating gastric adenocarcinomas and the results provide important new insights into the possible molecular mechanisms of the anticancer activity of E. humifusae.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.10
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• pp.4469-4475
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• 2015

Transient receptor potential melastain 7 (TRPM7) is a bifunctional protein with dual structure of both ion channel and protein kinase, participating in a wide variety of diseases including cancer. Recent researches have reported the mechanism of TRPM7 in human cancers. However, the correlation between TRPM7 and prostate cancer (PCa) has not been well studied. The objective of this study was to investigate the potential the role of TRPM7 in the apoptosis of PC-3 cells, which is the key cell of advanced metastatic PCa. In this study, we demonstrated the influence and potential function of TRPM7 on the PC-3 cells apoptosis induced by TNF-related apoptosis inducing-ligand (TRAIL). The study also found a novel up-regulated expression of TRPM7 in PC-3 cells after treating with TRAIL. Suppression of TRPM7 by TRPM7 non-specific inhibitors ($Gd^{3+}$ or 2-aminoethoxy diphenylborate (2-APB) ) not only markedly eliminated TRPM7 expression level, but also increased the apoptosis of TRAIL-treated PC-3 cells, which may be regulated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway accompany with up-regulated expression of cleaved Caspase-3, (TRAIL-receptor 1, death receptors 4) DR4, and (TRAIL-receptor 2, death receptors 5) DR5. Taken together, our findings strongly suggested that TRPM7 was involved in the apoptosis of PC-3 cells induced by TRAIL, indicating that TRPM7 may be applied as a therapeutic target for PCa.

• Journal of Life Science
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• v.22 no.5
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• pp.697-701
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• 2012

Activated protein C (APC) has an anticoagulant effect and a non-hemostatic effect such as regulation of cell metastasis and modulation of inflammation. In this study, we investigated whether APC could modulate apoptosis in cancer cells. Tumor necrosis factor (TNF)-${\alpha}$, cyclohexamide, and FAS markedly induced apoptosis in human renal carcinoma Caki cells. When Caki cells were pretreated with APC, the percentage of death receptor-induced apoptosis did not change. Furthermore, we checked the effect of APC on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human glioma T98G and human breast carcinoma MDA231 cells. APC also had no effect on TRAIL-induced apoptosis in both cell lines. However, pretreatment with APC inhibited combination treatment (kahweol plus TRAIL and kahweol plus melatonin)-induced apoptosis and PARP cleavage in Caki cells. Taken together, our results suggest that APC can modulate anti-cancer therapeutic efficiency.