• The Korean Journal of Physiology and Pharmacology
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• 제12권5호
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• pp.225-230
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• 2008

Netrins are secreted molecules and involved in axon guidance, cell migration and tumor development. Recent studies revealed that netrins perform novel functions in such processes as epithelial development and angiogenesis without operating through the classical netrin receptors, DCC (Deleted in Colorectal Cancer) and Unc5h. In the present study, we investigated the roles of netrin-1 and its receptors in cell spreading of human glioblastoma cells, and found that netrin-1 haptotactically enhanced fibronectin-induced cell spreading and focal adhesion formation in U373 glioblastoma cells. Netrin-1 binding to the U373 cell membrane was blocked by an antibody against ${\alpha}v$ integrin subunit, but not by an anti-DCC or anti-Unc5h antibody. In addition, enhancement of the fibronectin response by netrin-1 was abrogated by a function blocking antibody against integrin ${\alpha}v{\beta}3$. Since the ${\alpha}v$ subunit of the integrin family plays an important role in the pathophysiological aspects of cell migration, including tumor angiogenesis and metastasis, our data provide important insight into the molecular mechanism of netrin function.

• 생명과학회지
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• 제24권10호
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• pp.1137-1143
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• 2014

Doxorubicin은 광범위한 암을 치료하는데 사용되는 일반적인 항암제이지만, 내인성 산화질소 생성량과 Doxorubicin의 항암 효과의 상관 관계에 대해서는 아직 명확하게 밝혀지지 않았다. 본 연구에서는 인간 대장암 세포에서 Doxorubicin의 항암 활성에 내인성 산화질소가 미치는 영향을 확인하고자 하였다. HCT116 (p53-WT)과 HT29 (p53-MUT) 세포에서 Doxorubicin 처리에 의해 세포 생존율의 차이를 보였으며, NMA 병행처리는 Doxorubicin의 효과를 감소시켰음을 확인할 수 있었다. 추가 연구를 통해 HCT116과 HT29 세포에서 sub-$G_1$ 기의 세포 빈도와 DNA 단편화의 결과를 통해 내인성 산화질소가 Doxorubicin에 의한 apoptosis를 조절하는 것을 확인하였다. 이러한 결과는 인간 대장암 세포에서 내인성 산화질소와 IAP 발현, p53의 상태에 따른 조절이 Doxorubicin에 의해 유도된다는 것을 보여주며, 이러한 메커니즘은 대장암에서 화학요법의 효율을 향상시키기 위한 전략적인 표적으로 이용할 수 있을 것으로 생각된다.

• 동의생리병리학회지
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• 제20권6호
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• pp.1572-1575
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• 2006

Water extract from Cnidii Rhizoma (CRW) was tested for colon cancer chemopreventive activity by measuring the induction of phase II detoxification enzyme activity [quinone reductase (QR) and glutathione S-transferase (GST)] and glutathion (GSH) levels and ornithine decarboxylase (ODC) activity in cultured human colorectal adenocarcinoma HT-29 cells. CRW inhibited cell proliferation in cultured HT-29 cells. CRW induced QR activity in a dose-dependent manner in a concentration range of 0.1${\sim}$5.0 $mg/m{\ell}$. GST activity was also induced with the treatment of CRW in HT-29 cells. In addition GSH levels was increased with CRW. CRW inhibited ODC activity, a key enzyme of polyamine biosynthesis, which is enhanced in tumor promotion. These results suggest that CRW has colon cancer chemopreventive activity by increasing phase II enzyme activity and GSH levels and inhibiting ODC activity in vitro.

• 한국축산식품학회지
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• 제38권3호
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• pp.615-628
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• 2018

Preserved egg, a kind of alkaline-fermented food, is a traditional egg product in China. Here, we investigated the nutritional functions of preserved eggs by in vivo and in vitro experiments. The results of in vivo studies showed that the levels of triglycerides (TG), total cholesterol (TCHO) and low-density lipoprotein cholesterol/high density lipoprotein cholesterol (LDL-C/HDL-C) were significantly decreased (p<0.05) in the liver of rats treated with preserved eggs. Meanwhile, the levels of two important cancer markers, interleukin-6 (IL-6) and tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), were also significantly decreased (p<0.05) in treated rats. In vitro studies were performed on Caco-2 cells, a human epithelial colorectal adenocarcinoma cell line. It demonstrated that the gastrointestinal (GI) digests of preserved eggs significantly accelerated (p<0.05) the apoptosis by upregulating caspase-3 in the Caco-2 cells. Besides, after treated with preserved eggs, the half maximal inhibitory concentration (IC50) of preserved eggs digests to Caco-2 cells was 5.75 mg/mL, indicating the significant inhibition of cell proliferation provided by preserved eggs (p<0.05). The results shown in this study demonstrated that preserved eggs may be a novel functional food involved with antilipemic, anti-inflammatory activity as well as the effect on accelarating the apoptosis of Caco-2 cells.

• BMB Reports
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• 제39권6호
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• pp.649-655
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• 2006

The NSAID activated gene (NAG-1), a member of the TGF-$\beta$ superfamily, is involved in tumor progression and development. The over-expression of NAG-1 in cancer cells results in growth arrest and increase in apoptosis, suggesting that NAG-1 has anti-tumorigenic activity. This conclusion is further supported by results of experiments with transgenic mice that ubiquitously express human NAG-1. These transgenic mice are resistant to the development of intestinal tumors following treatment with azoxymethane or by introduction of a mutant APC gene. In contrast, other data suggest a pro-tumorigenic role for NAG-1, for example, high expression of NAG-1 is frequently observed in tumors. NAG-1 may be like other members of the TGF-$\beta$ superfamily, acting as a tumor suppressor in the early stages, but acting pro-tumorigenic at the later stages of tumor progression. The expression of NAG-1 can be increased by treatment with drugs and chemicals documented to prevent tumor formation and development. Most notable is the increase in NAG-1 expression by the inhibitors of cyclooxygenases that prevent human colorectal cancer development. The regulation of NAG-1 is complex, but these agents act through either p53 or EGR-1 related pathways. In addition, an increase in NAG-1 is observed in inhibition of the AKT/GSK-$3{\beta}$ pathway, suggesting NAG-1 alters cell survival. Thus, NAG-1 expression is regulated by tumor suppressor pathways and appears to modulate tumor progression.

• The Korean Journal of Physiology and Pharmacology
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• 제18권6호
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• pp.509-516
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• 2014

Radiation therapy for variety of human solid tumors utilizes mechanism of cell death after DNA damage caused by radiation. In response to DNA damage, cytochrome c was released from mitochondria by activation of pro-apoptotic Bcl-2 family proteins, and then elicits massive $Ca^{2+}$ release from the ER that lead to cell death. It was also suggested that irradiation may cause the deregulation of $Ca^{2+}$ homeostasis and trigger programmed cell death and regulate death specific enzymes. Thus, in this study, we investigated how cellular $Ca^{2+}$ metabolism in RKO cells, in comparison to radiation-resistant A549 cells, was altered by gamma (${\gamma}$)-irradiation. In irradiated RKO cells, $Ca^{2+}$ influx via activation of NCX reverse mode was enhanced and a decline of $[Ca^{2+}]_i$ via forward mode was accelerated. The amount of $Ca^{2+}$ released from the ER in RKO cells by the activation of $IP_3$ receptor was also enhanced by irradiation. An increase in $[Ca^{2+}]_i$ via SOCI was enhanced in irradiated RKO cells, while that in A549 cells was depressed. These results suggest that ${\gamma}$-irradiation elicits enhancement of cellular $Ca^{2+}$ metabolism in radiation-sensitive RKO cells yielding programmed cell death.

• 대한한의학방제학회지
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• 제14권2호
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• pp.21-32
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• 2006

The purpose of this study was to investigate the effect of Imyosan on apoptosis in human colorectal cancer HCT116 cells. Phellodendron amurense Rupr. and Atratylodes lancea D.C. compose Imyosan. First of all, to study the cytotoxic effect of methanol extract of Imyosan (IMS-MeOH) on HCT116 cells, the cells were treated with various concentrations of IMS-MeOH and then cell viability was determined by XTT reduction method. IMS-MeOH reduced viability of HCT116 cells in a dose and time-dependent manner. To confirm the induction of apoptosis, the c1eavage of poly ADP-ribose polymerase (PARP), a substrate for caspase-3 and a typical sign of apoptosis, and the activation of caspase-3, procaspase-8 and procaspase-9 were examined by western blot analysis. IMS-MeOH decreased procaspase-3, procaspase-8 and procaspase-9 levels in a dose-dependent manner and induced the clevage of PARP. IMS-MeOH triggered the mitochondrial apoptotic signaling by increasing the release of cytochrome c from mitochondria to cytosol. Furthermore, IMS-MeOH also downregulated the anti-apoptotic Bcl-2 and upregulated the pro-apoptotic-Bax. Therefore, these results suggest that IMS-MeOH induced HCT1l6 cell death through the mitochondrial pathway. To explore whether the activities of caspases was required for induction of apoptosis by IMS-MeOH, caspase-3, -8, -9 activity measured by using substrates, respectively. IMS-MeOH increased caspase-3, -8, -9 activity. Co-treatment with inhibitors of caspase-3, -8, -9 and IMS-MeOH significantly blocked IMS-MeOH-triggered apoptosis in HCT1l6 cells. These results suggest that IMS-MeOH induces caspases-mediated apoptosis.

• BMB Reports
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• 제51권6호
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• pp.296-301
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• 2018

Mitochondrial DNA (mtDNA) mutations are often observed in various cancer types. Although the correlation between mitochondrial dysfunction and cancer malignancy has been demonstrated by several studies, further research is required to elucidate the molecular mechanisms underlying accelerated tumor development and progression due to mitochondrial mutations. We generated an mtDNA-depleted cell line, ${\rho}^0$, via long-term ethidium bromide treatment to define the molecular mechanisms of tumor malignancy induced by mitochondrial dysfunction. Mitochondrial dysfunction in ${\rho}^0$ cells reduced drug-induced cell death and decreased the expression of pro-apoptotic proteins including p53. The p53 expression was reduced by activation of nuclear $factor-{\kappa}B$ that depended on elevated levels of free calcium in $HCT116/{\rho}^0$ cells. Overall, these data provide a novel mechanism for tumor development and drug resistance due to mitochondrial dysfunction.

• Asian Pacific Journal of Cancer Prevention
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• 제14권3호
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• pp.2113-2118
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• 2013

Aim and Background: Cervical cancer remains the third most common cancer in women globally after breast and colorectal cancer. Well-characterized biomarkers are necessary for early diagnosis and to predict metastatic progression and effective therapy. MiRNAs can regulate gene expression, cell growth, differentiation and apoptosis by targeting mRNAs for translational repression or degradation in tumor cells. The present study was conducted to assess expression of miR93, miR200a, RECK, MMP2, MMP9 in invasive cervical carcinoma, and analyze their clinical significance. Method: A total of 116 patients with invasive cervical carcinoma and 100 patients undergoing hysterectomy for benign lesions were retrospectively examined. Quantitative real-time PCR was performed to determine expression of miR93 and miR200a while RECK, MMP2, MMP9 and MVD were assessed by immunohistochemical staining. Results: Cervical carcinoma patients demonstrated up-regulation of miR-93, miR-200a, MMP2 and MMP9, with down-regulation of RECK as compared to benign lesion tissues. RECK was significantly inversely related to invasion and lymphatic metastasis. The 5-year survival rate for patients with strong RECK expression was significantly higher than that with weakly expressing tumors. Conclusion: MiR-93 and miR-200a are associated with metastasis and invasion of cervical carcinoma. Thus together with RECK they are potential prognostic markers for cervical carcinoma. RECK cooperating with MMP2, MMP9 expression is a significant prognostic factor correlated with long-term survival for patients with invasive cervical carcinoma.

• Journal of Ginseng Research
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• 제42권3호
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• pp.288-297
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• 2018

Background: The incidence of colorectal cancer (CRC) is increasing, with metastasis of newly diagnosed CRC reported in a large proportion of patients. However, the effect of Korean Red Ginseng extracts (KRGE) on epithelial to mesenchymal transition (EMT) in CRC is unknown. Therefore, we examined the mechanisms by which KRGE regulates EMT of CRC in hypoxic conditions. Methods: Human CRC cell lines HT29 and HCT116 were incubated under hypoxic (1% oxygen) and normoxic (21% oxygen) conditions. Western blot analysis and real-time PCR were used to evaluate the expression of EMT markers in the presence of KRGE. Furthermore, we performed scratched wound healing, transwell migration, and invasion assays to monitor whether KRGE affects migratory and invasive abilities of CRC cells under hypoxic conditions. Results: KRGE-treated HT29 and HCT116 cells displayed attenuated vascular endothelial growth factor (VEGF) mRNA levels and hypoxia-inducible $factor-1{\alpha}$ ($HIF-1{\alpha}$) protein expression under hypoxic conditions. KRGE repressed Snail, Slug, and Twist mRNA expression and integrin ${\alpha}V{\beta}6$ protein levels. Furthermore, hypoxia-repressed E-cadherin was restored in KRGE-treated cells; KRGE blocked the invasion and migration of colon cancer cells by repressing $NF-{\kappa}B$ and ERK1/2 pathways in hypoxia. Conclusions: KRGE inhibits hypoxia-induced EMT by repressing $NF-{\kappa}B$ and ERK1/2 pathways in colon cancer cells.