• Journal of Ginseng Research
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• v.45 no.1
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• pp.134-148
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• 2021

Background: Lung cancer has a high incidence worldwide, and most lung cancer-associated deaths are attributable to cancer metastasis. Although several medicinal properties of Panax ginseng Meyer have been reported, the effect of ginsenosides Rk1 and Rg5 on epithelial-mesenchymal transition (EMT) stimulated by transforming growth factor beta 1 (TGF-β1) and self-renewal in A549 cells is relatively unknown. Methods: We treated TGF-β1 or alternatively Rk1 and Rg5 in A549 cells. We used western blot analysis, real-time polymerase chain reaction (qPCR), wound healing assay, Matrigel invasion assay, and anoikis assays to determine the effect of Rk1 and Rg5 on TGF-mediated EMT in lung cancer cell. In addition, we performed tumorsphere formation assays and real-time PCR to evaluate the stem-like properties. Results: EMT is induced by TGF-β1 in A549 cells causing the development of cancer stem-like features. Expression of E-cadherin, an epithelial marker, decreased and an increase in vimentin expression was noted. Cell mobility, invasiveness, and anoikis resistance were enhanced with TGF-β1 treatment. In addition, the expression of stem cell markers, CD44, and CD133, was also increased. Treatment with Rk1 and Rg5 suppressed EMT by TGF-β1 and the development of stemness in a dose-dependent manner. Additionally, Rk1 and Rg5 markedly suppressed TGF-β1-induced metalloproteinase-2/9 (MMP2/9) activity, and activation of Smad2/3 and nuclear factor kappa B/extra-cellular signal regulated kinases (NF-kB/ERK) pathways in lung cancer cells. Conclusions: Rk1 and Rg5 regulate the EMT inducing TGF-β1 by suppressing the Smad and NF-κB/ERK pathways (non-Smad pathway).

• YAKHAK HOEJI
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• v.55 no.1
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• pp.49-55
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• 2011

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is one of the promising anti-cancer agent because of its ability to selectively induce apoptosis in tumor cell lines but not in normal cells. However, TRAIL resistance has been reported in some cancer cells including hepatocarcinoma cells. Therefore, studies of agents that sensitize TRAIL-resistant cancer cells could be a effective therapeutic approach in cancer management. In our study, we examined the effect of combination of TRAIL with apigenin in human hepatocellular carcinoma cells. As a result, the combined use of TRAIL and apigenin significantly enhanced the cytotoxicity in PLC-PRF5 cells. Flow cytometry analysis after annexin V-FITC/PI dual staining showed that this increase of cell cytotoxicity was related to enhanced apoptosis in combined treatment of TRAIL with apigenin. Furthermore, synergistic induction of apoptosis was also confirmed by observation of morphological changes and annexin V-FITC/PI fluorescence. Our findings suggests that apigenin has the potential to improve the efficiency of TRAIL-based therapies in human hepatocellular carcinoma cells. Further study is needed to reveal the molecular mechanisms of this combined therapy.

• Applied Biological Chemistry
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• v.23 no.3
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• pp.189-197
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• 1980

Effect of monoterpene composition in pine needles on the susceptibility to pine gall midge (Thecodiplosis japonensis Uchida et Inouye) has been pursued. The pines studied include 5 susceptible and 2 resistant species. Also included were severely damaged or unaffected P. densiflora in the pine gall midge affected region. From the needles of the pine trees, 9 monoterpenes were identified by GLC. No correlationship, was found to hold in the monoterpene composition between pine gall midge susceptible and nonsusceptible pine species. Concentrations of limonene, however, gradually increased following oviposition in the unaffected P. densiflora while the concentrations of the monoterpene remained constant in the damaged P. densiflora. Effect of high limonene concentration in the needles of P. densiflora is discussed as a possible factor inducing resistance toward the pest in the unaffected Pinus densiflora.

• BMB Reports
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• v.51 no.12
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• pp.660-665
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• 2018

Human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab and lapatinib are used to treat HER2-positive breast and gastric cancers. However, as with other targeted therapies, intrinsic or acquired resistance to HER2 inhibitors presents unresolved therapeutic problems for HER2-positive gastric cancer. The present study describes investigations with AUY922, a heat shock protein 90 (HSP90) inhibitor, in primary lapatinib-resistant (ESO26 and OE33) and lapatinib-sensitive gastric cancer cells (OE19, N87, and SNU-216) harboring HER2 amplification/over-expression. In order to investigate whether AUY922 could overcome intrinsic and acquired resistance to HER2 inhibitors in HER2-positive gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (OE19/LR and N87/LR) by continuous exposure to lapatinib in vitro. We found that activation of HER2 and protein kinase B (AKT) were key factors in inducing intrinsic and acquired lapatinib-resistant gastric cancer cell lines, and that AUY922 effectively suppressed activation of both HER2 and AKT in acquired lapatinib-resistant gastric cancer cell lines. In conclusion, AUY922 showed a synergistic anti-cancer effect with lapatinib and sensitized gastric cancer cells with intrinsic resistance to lapatinib. Dual inhibition of the HSP90 and HER2 signaling pathways could represent a potent therapeutic strategy to treat HER2-positive gastric cancer with intrinsic and acquired resistance to lapatinib.

• Journal of Acupuncture Research
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• v.25 no.3
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• pp.41-51
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• 2008

Objectives : This study is to evaluate Effect of Inhibition Macrophage Migration Inhibitory Factor(MIF) activation by Hominis Placenta Herbal Acupuncture(HPA) on Rheumatic Arthritis(RA). Hominis Placenta is the placenta of healthy human, which is vital-strengthening medical stuff. In recent years, Hominis Placenta applied to chronic diseases because it makes us more resistance to diseases. Therefore it is supposed that HPA is effective on RA, a kind of autoimmune disease. When RA is induced, MIF is activated, too. MIF affects the process of inflammatory disease including RA. Methods : In order to investigate the effect of Hominis Placenta extraction on MIF(early RA inducing cytokine) and MMP(Matrix Metallo Proteinase)-9 mRNA expression by means of Reverse Transcriptase- Polymerase Chain Reaction(RT-PCR). In this study, we investigated the effect of Hominis Placenta extraction on MIF(early RA inducing cytokine) and MMP-9 mRNA expression by means of RT-PCR. Besides we investigated changing of MIF in synovial membrane and, Interleukin-6 receptor(IL-6R)-$\alpha$(pro-inflammatory cytokine), Signal transducers and activators of transcription(STAT)-3, MMP-9 after treating mouse, which is artificially attacked with RA, with HPA on its $ST_{35}$, LE201 in vivo. Results : 1. As a result of treating Lipopolysaccharide(LPS)-stimulated Raw246.7cell with HPA, MIF(RA related cytokine) and MMP-9 mRNA expression is reduced in vitro. And this reaction is concentration-dependatant. 2. In synovial membrane of the mice treated with HPA, inhibition of MIF, IL-6R-$\alpha$, STAT3 & MMP-9 activation is observed in vivo. Conclusions : From the above results, it might be suggested that HPA mitigate tissue damage originated from RA, because it intercepts the early process of by inhibition MIF activity.

• Molecules and Cells
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• v.43 no.12
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• pp.975-988
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• 2020

Hypoxia plays important roles in cancer progression by inducing angiogenesis, metastasis, and drug resistance. However, the effects of hypoxia on long noncoding RNA (lncRNA) expression have not been clarified. Herein, we evaluated alterations in lncRNA expression in lung cancer cells under hypoxic conditions using lncRNA microarray analyses. Among 40,173 lncRNAs, 211 and 113 lncRNAs were up- and downregulated, respectively, in both A549 and NCI-H460 cells. Uroplakin 1A (UPK1A) and UPK1A-antisense RNA 1 (AS1), which showed the highest upregulation under hypoxic conditions, were selected to investigate the effects of UPK1A-AS1 on the expression of UPK1A and the mechanisms of hypoxia-inducible expression. Following transfection of cells with small interfering RNA (siRNA) targeting hypoxia-inducible factor 1α (HIF-1α), the hypoxia-induced expression of UPK1A and UPK1A-AS1 was significantly reduced, indicating that HIF-1α played important roles in the hypoxia-induced expression of these targets. After transfection of cells with UPK1A siRNA, UPK1A and UPK1A-AS1 levels were reduced. Moreover, transfection of cells with UPK1A-AS1 siRNA downregulated both UPK1A-AS1 and UPK1A. RNase protection assays demonstrated that UPK1A and UPK1A-AS1 formed a duplex; thus, transfection with UPK1A-AS1 siRNA decreased the RNA stability of UPK1A. Overall, these results indicated that UPK1A and UPK1A-AS1 expression increased under hypoxic conditions in a HIF-1α-dependent manner and that formation of a UPK1A/UPK1A-AS1 duplex affected RNA stability, enabling each molecule to regulate the expression of the other.

• Research in Plant Disease
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• v.28 no.2
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• pp.82-91
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• 2022

Recently, several in vitro studies have reported antiviral activity of agents of systemic acquired resistance against plant virus infection, but the approach has not been applied in a wide range of agricultural fields. The objective of this study was to evaluate the inhibitory effect of the exogenous application of salicylic acid (SA), chitosan (CH), or eugenol (EG) in tomato yellow leaf curl virus (TYLCV) infection of greenhouse-grown tomato plants. In vitro, the initial time of symptom was observed in TYLCV-infected plants (VP) of the resistant cultivar 'Superdotaerang' at 12 days post inoculation (dpi) after application of antiviral agents. At 32 dpi, the disease rate of TYLCV in the CHT+VP (0.1% chitosan and virus infected control) treated plants was 87.5%, lower than that of the other treatment. However, the virus content in the CHT+VP treated plants was higher than those of the other treatments, and SA, EG, and CH did not show significant effect on plant height or shoot and root fresh weight. Our results from summer-cultivated greenhouse-grown tomatoes show that none of the tested agents had an inhibitory activity on viral infection or yield of tomato 'Dotaerangsola'cultivar. In contrast, all treated 'TY Giants' cultivars that possessed TYLCV resistance genes Ty-1 and Ty-3a did not show typical symptoms and the virus content was remarkably lower than those in the TYLCV treated plants in 'Superdotaerang'. The results of this research indicated that the planting of resistant tomato cultivars was effective method instead of using SA, EG, and CH (known as resistance-inducing factors for control) of TYLCV in the field.

• Journal of Acupuncture Research
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• v.31 no.2
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• pp.87-98
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• 2014

Objectives : We investigated whether snake venom toxin(SVT) from Vipera lebetina turanica sensitizes HT29 human epithelial colorectal cancer cells to tumor necrosis factor(TNF)-related apoptosis-inducing ligand(TRAIL) induced apoptosis in cancer cells. Methods : Cell viability assay was used to assess the inhibitory effect of TRAIL on cell growth of HT29 human colorectal cancer cells. And 6-diamidino-2-phenylindole(DAPI), terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay(TUNEL) staining assay were used to evaluate cell-apoptosis. Western blot analysis were conducted to observe apoptosis related proteins and death receptor. To assess whether the synergized inhibitory effect of SVT and TRAIL on reactive oxygen species(ROS) generation was reversed by strong anti-oxidative agent. Results : SVT with TRAIL inhibited HT29 cell growth different from TRAIL alone. Consistent with cell growth inhibition, the expression of TRAIL receptors; Expression of death receptor(DR)4 and DR5 was significantly increased and intrinsic pro-apoptotic cleaved caspase-3, -9 was subsequently increased together with increase of Bax/Bcl-2 ratio and extrinsic pro-apototic caspase-8 was also activated. In addition, the expression of anti-apoptotic survival proteins, a marker of TRAIL resistance(eg, cFLIP, survivin, X-linked inhibitor of apoptosis protein(XIAP) and Bcl-2) was suppressed by the combination treatment of SVT and TRAIL. Pretreatment with the ROS scavenger N-acetylcysteine abolished the SVT and TRAIL-induced upregulation of DR4 and DR5 expression and expression of the intrinsic pro-apoptotic caspase-3 and-9. Conclusion : The collective results suggest that SVT facilitates TRAIL-induced apoptosis in $HT_{29}$ human epithelial colorectal cancer cells through up-regulation of the TRAIL receptors; DR4 and DR5 and consecutive induction of bilateral apoptosis via regulating apoptosis related 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.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.5977-5982
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• 2014

Research over the years has progressively shown substantial broadening of the tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL)-mediated signaling landscape. Increasingly it is being realized that pancreatic cancer is a multifaceted and genomically complex disease. Suppression of tumor suppressors, overexpression of oncogenes, epigenetic silencing, and loss of apoptosis are some of the extensively studied underlying mechanisms. Rapidly accumulating in vitro and in vivo evidence has started to shed light on the resistance mechanisms in pancreatic cancer cells. More interestingly a recent research has opened new horizons of miRNA regulation by DR5 in pancreatic cancer cells. It has been shown that DR5 interacts with the core microprocessor components Drosha and DGCR8, thus impairing processing of primary let-7. Xenografting DR5 silenced pancreatic cancer cells in SCID-mice indicated that there was notable suppression of tumor growth. There is a paradigm shift in our current understanding of TRAIL mediated signaling in pancreatic cancer cells that is now adding new layers of concepts into the existing scientific evidence. In this review we have attempted to provide an overview of recent advances in TRAIL mediated signaling in pancreatic cancer as evidenced by findings of in vitro and in vivo analyses. Furthermore, we discuss nanotechnological advances with emphasis on PEG-TRAIL and four-arm PEG cross-linked hyaluronic acid (HA) hydrogels to improve availability of TRAIL at target sites.