• Biomolecules & Therapeutics
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• 제29권1호
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• pp.64-72
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• 2021

Renal cell carcinoma (RCC) is likely to metastasize to other organs, and is often resistant to conventional chemotherapies. Thymoquinone (TQ), a phytochemical derived from the seeds of Nigella sativa, has been shown to inhibit migration and metastasis in various cancers. In this study, we assessed the effect of TQ on the migratory activity of human RCC Caki-1 cells. We found that treatment with TQ reduced the proteolytic activity of matrix metalloproteinase-9 (MMP-9) in Caki-1 cells. TQ significantly repressed prostaglandin E2 (PGE2) production, its EP2 receptor expression as well as the activation of Akt and p38, the wellknown upstream signal proteins of MMP-9. In addition, treatment with butaprost, a PGE2 agonist, also induced MMP-9 activity and migration/invasion in Caki-1 cells. Moreover, pharmacological inhibitors of PI3K/Akt and p38 remarkably attenuated butaprost-induced Caki-1 cell migration and invasion, implying that activation of PI3K/Akt and p38 is a bridge between the PGE2-EP2 axis and MMP-9-dependent migration and invasion. Taken together, these data suggest that TQ is a promising anti-metastatic drug to treat advanced and metastatic RCC.

• 한국축산식품학회지
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• 제35권4호
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• pp.507-514
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• 2015

Deer velvet antler (DVA) is one of the most popular medicines in China. Numerous studies have demonstrated that velvet antler possess biological effects. However, data regarding its anti-migration activity on prostate cancer is scarce. In this study, we investigated the inhibitory effect of top DVA (T-DVA) on the expression of prostate-specific antigen (PSA) and migration-related genes in the human prostate cancer cell, LNCaP. The T-DVA down-regulated the expression of PSA. In addition, the Radius^TM assay revealed that T-DVA inhibited the migration behavior of prostate cancer cells. Furthermore, the expression of matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF) was also decreased with T-DVA. On the contrary, T-DVA increased the tissue inhibition of metallo-proteinase (TIMP)-1 and (TIMP)-2. Taken together, our findings indicate that the T-DVA possesses anti-migration activity on prostate cancer cells. This is the first study of DVA to report the anti-migration activity on prostate cancer.

• The Korean Journal of Physiology and Pharmacology
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• 제27권3호
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• pp.257-265
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• 2023

Kidney ischemia/reperfusion (I/R) injury, a common cause of acute kidney injury (AKI), is associated with the migration of inflammatory cells into the kidney. Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho family of small GTPase, plays an important role in inflammatory cell migration by cytoskeleton rearrangement. Here, we investigated the role of Rac1 on kidney I/R injury and macrophage migration. Male mice were subjected to either 25 min of bilateral ischemia followed by reperfusion (I/R) or a sham operation. Some mice were administrated with either NSC23766, an inhibitor of Rac1, or 0.9% NaCl (vehicle). Kidney damage and Rac1 activity and expression were measured. The migration and lamellipodia formation of RAW264.7 cells, mouse monocyte/macrophage, induced by monocyte chemoattractant protein-1 (MCP-1, a chemokine) were determined using transwell migration assay and phalloidin staining, respectively. In sham-operated kidneys, Rac1 was expressed in tubular cells and interstitial cells. In I/R-injured kidneys, Rac1 expression was decreased in tubule cells in correlation with the damage of tubular cells, whereas Rac1 expression increased in the interstitium in correlation with an increased population of F4/80 cells, monocytes/macrophages. I/R increased Rac1 activity without changing total Rac1 expression in the whole kidney lysates. NSC23766 administration blocked Rac1 activation and protected the kidney against I/R-induced kidney damage and interstitial F4/80 cell increase. NSC23766 suppressed monocyte MCP-1-induced lamellipodia and filopodia formation and migration of RAW 264.7 cells. These results indicate Rac1 inhibition protects the kidney against I/R via inhibition of monocytes/macrophages migration into the kidney.

• Journal of Acupuncture Research
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• 제24권5호
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• pp.23-32
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• 2007

Objectives : Angiogenesis consists of the proliferation, migration, and differentiation of endothelial cells, and angiogenic factors and matrix protein interactions modulate this process. The aim of this study was to determine whether herbs medicine(KHBJs) could induce angiogenic activity in human umbilical vein endothelial cells(HUVECs). Methods : The angiogenic activity of KHBJs were evaluated by proliferation using BrdU assay, chemotactic migration assay, tube formation assay, and measurement of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor(VEGF) in HUVECs. Also, In order to identify enhance angiogenic activity by activity guided fractionation, the angiogenic activity of fractions of KHBJs such as KHBJB or KHBJR were evaluated in vitro and in vivo Matrigel plug angiogenesis asaay. Results : About 9 KHBJs significantly increased HUVECs proliferation in a dose-dependent manner. In addition, 9 herbs medicine(KHBJs) increased migration and tube-like formation in HUVECs. Interestingly the expression of bFGF and VEGF, an angiogenesis-inducing growth factor, were dose-dependently increased by KHBJs. However, angiogenic activity of fractionated KHBJs(KHBJB or KHBJR) not enhanced more than KHBJs in HUVECs and Matrigel plug in vivo angiogenesis assay. Conclusions : 9 KHBJs significantly induces angiogenesis in in vitro and in vivo. These results suggest that 9 KHBJs potent angiogenic agents and promising drug for the induction of neovascularization.

• 대한의생명과학회지
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• 제10권2호
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• pp.143-151
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• 2004

Matrix metalloproteinases (MMPs) are capable of degrading extracellular matrix, a process that is necessary for angiogenesis, tumor invasion and metastasis. Platelet-activating factor (PAP) increases angiogenesis, tumor growth and metastasis through nuclear factor (NF)-$\kappa$B activation. Based on these facts, the involvement of MMPs in PAF-induced pulmonary metastasis was investigated in murine sarcoma cells, MMSV-BALB/3T3. Messenger RNA expression and enzymatic activity of MMP-9 were assessed by RT-PCR and zymography, and cell migration and metastasis were done for the detection of MMP-9 functional activity. PAP induced mRNA expression and enzymatic activity of MMP-9, and its effects were either inhibited by the PAP antagonist, WEB 2170 or by the NF-$\kappa$B inhibitor, parthenolide, or p65 antisense oligonucleotide in a dose-dependent manner. In addition, PAF induced promoter activity of MMP-9, which was inhibited by WEB 2170, phenanthroline, NAC, PDTC. These results indicate that PAF induces mRNA expression and enzymatic activity of MMP-9 in NF-$\kappa$B dependent manner. Cell migration assay showed that PAF induced MMSV-BALB/3T3 migration, and its effect was significantly inhibited by treatment with phenanthroline. PAF enhanced pulmonary metastasis of murine sarcoma cells, MMSV-BALB/3T3 was also reduced by phenanthroline. These results suggest that PAF-enhanced cell migration and pulmonary metastasis is mediated through the expression of MMP. In conclusion, It is suggested that PAF enhances pulmonary metastasis by inducing MMP-9 expression via the activation of NF-$\kappa$B.

• 동의생리병리학회지
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• 제23권2호
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• pp.480-487
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• 2009

Atherosclerosis, slow progressing inflammatory lesion in arteries, is one of the major causes of cardiovascular diseases. As mortality due to cardiovascular disease keeps increasing in Korea, researches on pathological mechanism of atherosclerosis may be beneficial in fighting against cardiovascular diseases. It is known that migration and MMP-9 secretion of Vascular Smooth Muscle Cell(VSMC) play a significant part in pathogenesis of atherosclerosis, although detailed mechanism of entire process is not clarified. We investigated whether the seeds of Trichosanthes kirilowii maxim (TS), inhibit migration and MMP-9 production of HASMC(human aortic SMC), which were induced by TNF-${\alpha}$ treatment. Migration assay showed that TS inhibited the migration of HASMC induced by TNF-${\alpha}$, in dose dependent manner. Also by Zymography MMP-9 production of HASMC was found to be reduced by TS, both in time and in dose dependent manner. Western blotting results suggest TS suppress activity of MAPkinases.

• 약학회지
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• 제35권3호
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• pp.165-173
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• 1991

Effects of eight flavonoids and their related compounds on leukocytes migration, superoxide anion production and lipid peroxidation in the phagocytosis of latex beads or E. coli by guinea pig peritoneal exudate cells were studied in vitro. It shows that most of flavonoids generally inhibited the leukocytes migration and production of superoxide anion and malonedialdehydes. Their inhibitory activities in the phagocytosis of latex beads had more active than that of E. coli. Quercetin has the most inhibitory activity in leukocytes migration and production of superoxide anion and lipid peroxides at the concentration of 1, 2 and 10 $\mu{M}$. Catechin and rutin at the concentration of 2 and 10 $\mu{M}$ inhibited significantly the production of superoxide anion and lipid peroxides. Flavone, catechin, naringin and rutin at the concentration of 2 and 10 $\mu{M}$ inhibited significantly the leukocytes migration.

• Biomolecules & Therapeutics
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• 제28권5호
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• pp.405-413
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• 2020

Fibroblast-like synoviocytes (FLS) play a crucial role in initiating rheumatoid arthritis. B-cell activating factor (BAFF) plays a role in FLS survival as well as in B cell maturation and maintenance. Here, we investigated whether tumor necrosis factor (TNF)-α-induced BAFF expression controls FLS migration and whether BAFF expression in FLS could be regulated by KR33426 which is the inhibitor of BAFF binding to BAFF receptors (BAFF-R) by using MH7A synovial cells transfected with the SV40 T antigen. More TNF-α-treated cells migrated compared to the control. TNF-α increased BAFF expression in FLS, significantly. FLS migration was inhibited by the transfection with BAFF-siRNA. KR33426 also inhibited BAFF expression increased by TNF-α treatment in FLS as judged by western blotting, PCR, and transcriptional activity assay. Kinases including JNK, p38 and Erk were activated by TNF-α treatment. While JNK and p38 were inhibited by KR33426 treatment, no changes in Erk were observed. Transcription factors including p65, c-Fos, CREB and SP1 were enhanced by TNF-α treatment. Among them, c-Fos was inhibited by KR33426 treatment. Small interference(si)-RNA of c-fos decreased BAFF transcriptional activity. FLS migration induced by TNF-α was inhibited by the transfection with BAFF-siRNA. KR33426 increased Twist, Snail, Cadherin-11 and N-Cadherin. In contrast, KR33426 decreased E-cadherin and TNF-α-enhanced CCL2. Taken together, our results demonstrate that synovial cell migration via CCL2 expression could be regulated by BAFF expression which is decreased by KR33426 and c-Fos-siRNA. It suggests for the first time that the role of BAFF-siRNA on FLS migration might be matched in the effect of KR33426 on BAFF expression.

• Asian Pacific Journal of Cancer Prevention
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• 제16권7호
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• pp.2719-2724
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• 2015

Objective: The aim of this study was to investigate the clinical significance of annexin a1 (ANXA1) and provide molecular evidence to support that decreased ANXA1 expression could enhance cancer migration and invasion in pancreatic ductal adenocarcinoma (PDAC). Materials and Methods: Immunohistochemistry of a tissue microarray with 162 surgically resected PDAC specimens was performed to examine the expression of ANXA1. We also investigated the relationship between ANXA1 expression and clinicopathological factors and prognosis of PDAC patients. We further studied the role of ANXA1 in PDAC cell proliferation, migration and invasion by cell proliferation assay, migration assay and matrigel invasion assay with reduced ANXA1 expression by RNAi. Western blotting was used to detect matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. We also detected MMP-9 enzyme activity by gelatin zymography. Results: Decreased expression of ANXA1 was significantly associated with poor differentiation, lymph node metastasis and advanced TNM stage of PDAC patients (p<0.05). Moreover, decreased expression of ANXA1 was correlated with poor survival (p<0.05). Furthermore, we found that ANXA1 knockdown inhibited cell proliferation, induced G1 phase cell cycle arrest, increased PDAC cell migration and invasion capacity compared with controls. In addition, Western blotting showed that ANXA1 knockdown increased the MMP-9 protein level and decreased TIMP-1 expression. Gelatin zymography showed that MMP-9 enzyme activity was also elevated. Conclusions: Negative ANXA1 expression is a most unfavorable prognostic factor for PDAC patients. ANXA1 knockdown inhibits cell proliferation by inducing G1 phase cell cycle arrest and increases migration and invasion of PDAC cells through up-regulating MMP-9 expression and activity, implying that ANXA1 may serve as a promising prognostic biomarker and therapeutic target for PDAC.

• Biomolecules & Therapeutics
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• 제20권2호
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• pp.165-170
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• 2012

Cell migration plays a role in many physiological and pathological processes. Reactive oxygen species (ROS) produced in mammalian cells influence intracellular signaling processes which in turn regulate various biological activities. Here, we investigated whether melanoma cell migration could be controlled by ROS production under normoxia condition. Cell migration was measured by wound healing assay after scratching confluent monolayer of B16F10 mouse melanoma cells. Cell migration was enhanced over 12 h after scratching cells. In addition, we found that ROS production was increased by scratching cells. ERK phosphorylation was also increased by scratching cells but it was decreased by the treatment with ROS scavengers, N-acetylcysteine (NAC). Tumor cell migration was inhibited by the treatment with PD98059, ERK inhibitor, NAC or DPI, well-known ROS scavengers. Tumor cell growth as judged by succinate dehydrogenase activity was inhibited by NAC treatment. When mice were intraperitoneally administered with NAC, the intracellular ROS production was reduced in peripheral blood mononuclear cells. In addition, B16F10 tumor growth was significantly inhibited by in vivo treatment with NAC. Collectively, these findings suggest that tumor cell migration and growth could be controlled by ROS production and its downstream signaling pathways, in vitro and in vivo.