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Lee J.H.,Korea Institute of Radiological and Medical Sciences | Lee J.H.,Biospectrum Life Science Institute | Shim J.W.,Korea Institute of Radiological and Medical Sciences | Choi Y.J.,Korea Institute of Radiological and Medical Sciences | And 2 more authors.
Oncology Reports | Year: 2013

The importance of anticancer stem cell research for breast cancer lies in the possibility of providing new approaches for an improved understanding of anticancer activity and cancer treatment. In this study, we demonstrated that the preclinical therapeutic efficacy of combining the multikinase inhibitor sorafenib with radiation was more effective in hypoxia-exposed breast cancer stem cells. We assessed cell viability and Annexin V to evaluate the combined effect of sorafenib and radiation following exposure to hypoxia. Our results showed that the synergistic cytotoxicity increased tumor cell apoptosis significantly and reduced cell proliferation in MDA-MB-231 and MCF-7 cells under hypoxic conditions compared to sorafenib or radiation alone in vitro. Additionally, the combined treatment induced G2/M cell cycle arrest. Notably, the combination of sorafenib and radiation eliminated CD44+CD24 -/low cells preferentially, which highly expressed hypoxia-inducible factor (HIF)-1α and effectively inhibited primary and secondary mammosphere formation in MDA-MB-231 cells. A combined effect on MDA-MB-231 cells in response to hypoxia was shown by inhibiting angiogenesis and metastasis by suppression of HIF-1α and matrix metalloproteinase-2 (MMP-2). Collectively, these results indicate that the efficacy of sorafenib combined with radiation for treating human breast cancer cells is synergistic and suggest a new therapeutic approach to prevent breast cancer progression by eliminating breast cancer stem cells. Source

Lee J.,Korea University | Jung E.,Biospectrum Life Science Institute | Hyun J.-W.,Jeju National University | Park D.,Korea University | Park D.,Biospectrum Life Science Institute
Journal of Cellular Biochemistry | Year: 2012

Ultraviolet A (UVA) irradiation is responsible for a variety of changes in cell biology. The purpose of this study was to investigate the effects of UVA irradiation on the stemness properties of human adipose tissue-derived mesenchymal stem cells (hAMSCs). Furthermore, we examined the UVA-antagonizing effects of L-cysteine ethylester hydrochloride (ethylcysteine) and elucidated its action mechanisms. The results of this study showed that UVA reduced the proliferative potential and stemness of hAMSCs, as evidenced by reduced proliferative activity in the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and downregulation of OCT4, NANOG, and SOX2, stemness-related genes. The mRNA level of hypoxia-inducible factor (HIF)-1α, but not HIF-2α was reduced by UVA. Moreover, the knockdown of HIF-1α using small interfering RNA (siRNA) for HIF-1α was found to downregulate stemness genes, suggesting that UVA reduces the stemness through downregulation of HIF-1α. In addition, we examined the mechanisms underlying the UVA-mediated effects and found that UVA induced production of prostaglandin (PG) E2 and 3'-5'-cyclic adenosine monophosphate (cAMP), and that this effect was mediated through activation of activating protein-1 (AP-1) and nuclear factor-κB (NF-κB). The UVA effects were antagonized by ethylcysteine, and the effects were found to be mediated by reduced production of PGE2 through the inhibition of JNK and p42/44 MAPK. Taken together, these findings show for the first time that UVA regulates the stemness of hAMSCs and its effects are mediated by downregulation of HIF-1α via the activation of PGE2-cAMP signaling. In addition, ethylcysteine may be used as an antagonizing agent to mitigate the effects of UVA. Copyright © 2012 Wiley Periodicals, Inc. Source

Lee J.,Korea University | Kim M.-H.,Biospectrum Life Science Institute | Lee J.-H.,Biospectrum Life Science Institute | Jung E.,Biospectrum Life Science Institute | And 2 more authors.
Journal of Cellular Biochemistry | Year: 2012

Adipocyte dysfunction is associated with the development of obesity. In this study, artemisinic acid, which was isolated from Artemisia annua L., inhibited adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells (hAMSCs) and its mechanism of action was determined. The mRNA levels of peroxidase proliferation-activated receptor (PPAR) Iγ and CCAAT/enhancer binding protein (C/EBP) α, late adipogenic factors, were reduced by artemisinic acid. Moreover, the mRNA levels of the PPAR Iγ target genes lipoprotein lipase, CD36, adipocyte protein, and liver X receptor were down-regulated by artemisinic acid. Artemisinic acid reduced expression of the C/EBP β́ gene without impacting C/EBP β. In addition, attempts to elucidate a possible mechanism underlying the artemisinic acid-mediated effects revealed that reduced expression of the C/EBP δ gene was mediated by inhibiting Jun N-terminal kinase (JNK). Additionally, artemisinic acid also reduced the expression of the adipogenesis-associated genes glucose transporter-4 and vascular endothelial growth factor. In addition to the interference of artemisinic acid with adipogenesis, artemisinic acid significantly attenuated tumor necrosis factor-α-induced secretion of interleukin-6 by undifferentiated hAMSCs, thus influencing insulin resistance and the inflammatory state characterizing obesity. Taken together, these findings indicate that inhibiting adipogenic differentiation of hAMSCs by artemisinic acid occurs primarily through reduced expression of C/EBP δ, which is mediated by the inhibition of JNK and suggest that aremisinic acid may be used as a complementary treatment option for obesity associated with metabolic syndrome. © 2012 Wiley Periodicals, Inc. Source

Lee J.,Biospectrum Life Science Institute | Jung E.,Biospectrum Life Science Institute | Kim Y.-S.,Biospectrum Life Science Institute | Park D.,Biospectrum Life Science Institute | And 3 more authors.
Archives of Dermatological Research | Year: 2013

We investigated the proliferative effect of a Acanthopanax senticosus extract (ASE) on human CD49f+/CD29+ keratinocytes and isolated phloridzin from A. senticosus as an active compound. In addition, the possible mechanisms of action were examined. We found that the ASE and phloridzin-promoted proliferation of CD49f+/CD29+ cells using MTT and Click-iT™ EdU flow cytometry assays. In addition, phosphorylation of the p44/42 MAPK (ERK), mTOR, p70 S6 kinase (p70S6K), S6 ribosomal protein (S6RP), eukaryotic initiation factor 4B (eIF4B), and eIF4E was stepwise induced in CD49f+/CD29+ cells. Furthermore, the ASE and phloridzin significantly induced the production of vascular endothelial growth factor and interleukin-6 in CD49f+/CD29+ cells. Similarly, ASE and phloridzin-induced phosphorylation of the mTOR/p70S6K/S6RP/eIF4B/eIF4E pathway was blocked in response to pretreatment with PD98059, a specific ERK inhibitor. Taken together, these results indicate that ASE and phloridzin-induced proliferation of CD49f+/CD29 + cells under serum-free conditions was mediated by the ERK-dependent mTOR pathway. © 2013 Springer-Verlag Berlin Heidelberg. Source

Lee J.,Biospectrum Life Science Institute | Lee J.,Seoul National University | Jung E.,Biospectrum Life Science Institute | Hwang W.,Biospectrum Life Science Institute | And 2 more authors.
Life Sciences | Year: 2010

Aims: Previous studies have shown that isorhamnetin has anti-adipogenic effects in mouse 3T3-L1 cells. This study was conducted to elucidate the inhibitory mechanisms of isorhamnetin during adipogenic differentiation of human adipose tissue-derived stem cells (hAMSCs). Main methods: The effect of isorhamnetin on adipogenic differentiation of hAMSCs was quantified by Oil Red O staining and a triglyceride assay. In addition, real-time PCR and Western blot were used to determine the expression of adipogenesis-related genes. Key findings: Isorhamnetin inhibited the adipocyte differentiation of hAMSCs. Additionally, when the effects of Wnt antagonists that promote adipogenesis were evaluated, isorhamnetin was found to down-regulate the mRNA levels of sFRP1 and Dkk1, but had no effect on the mRNA levels of sFRP2, sFRP3, sFRP4 and Dkk3. Isorhamnetin also inhibited the expression of Wnt receptor and co-receptor genes. Furthermore, isorhamnetin increased the protein levels of β-catenin, an effector molecule of Wnt signaling, but had no effect on the mRNA levels of β-catenin. The phosphorylation level of GSK 3β was also increased by isorhamnetin. These results were confirmed by the fact that the expression of c-myc, cyclin D1 and PPARβ, which are target genes of β-catenin, was upregulated by isorhamnetin. Moreover, isorhamnetin reduced the mRNA expression levels of C/EBPα and PPARγ which are known to be inhibited by c-myc or by cyclin D1 and PPARδ, respectively. Significance: Our results indicate that isorhamnetin inhibits the adipogenic differentiation of hAMSCs and that its mechanisms are mediated by the stabilization of β-catenin. © 2010 Elsevier Inc. Source

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