Full metadata record
DC Field | Value | Language |
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dc.contributor.advisor | 이인혜 | - |
dc.contributor.author | 김선영 | - |
dc.creator | 김선영 | - |
dc.date.accessioned | 2019-02-18T16:32:28Z | - |
dc.date.available | 2019-02-18T16:32:28Z | - |
dc.date.issued | 2019 | - |
dc.identifier.other | OAK-000000154317 | - |
dc.identifier.uri | http://dcollection.ewha.ac.kr/common/orgView/000000154317 | en_US |
dc.identifier.uri | https://dspace.ewha.ac.kr/handle/2015.oak/249135 | - |
dc.description.abstract | XAV939, which stabilizes the structure of axin, was developed as an anti-cancer drug to inhibit Wnt/β-catenin signaling pathway. In some cases, increased axin expression results in resistance to various anti-cancer drugs. To overcome this, we attempted to identify alternative drugs that are effective against XAV939-resistant cells. To that end, we screened various inhibitors and found that the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling reduces cell viability in association with a reduction in axin and β-catenin expression. Among the inhibitors, Bay11-7082 (Bay) was the most effective. Subsequent analysis revealed that Bay treatment, but not other NF-κB signaling inhibitors, induced proteasomal degradation of axin, β-catenin, and GSK-3β which might result in the reduction of Wnt signaling activity. This additional Bay11-7082 activity appeared to be more effective on cells with high Wnt activity, such as adenocarcinoma gastric cell line (AGS) cells. Cells (EC96) with suppressed Wnt signaling and high NF-κB signaling did not show proteasomal degradation of axin, β-catenin, and GSK-3β. Nevertheless, Bay11-7082 reduced the viability of two cells—AGS and EC96. Moreover, axin-expressing HeLa (HeLa-axin) showed reduced cell viability after Bay11-7082 treatment but not with XAV939, which suggested the efficient effect of Bay11-7082 on axin-expressing cells. Our results suggest that Bay11-7082 can be an effective anti-cancer agent against XAV939-resistant cancer cells. ;Wnt/b-catenin signaling을 inhibition 하기 위한 anti-cancer drug 으로 axin structure를 안정화시키는 tankyrase inhibitor XAV939가 개발되었다. 여러사례에서, axin expression 의 증가는 다양한 anti-cancer drug 에 대해 resistance을 초래한다. 이를 해결하기위해, XAV939-resistant cell 에 효과적인 다른 drug을 찾고자 하였다. 다양한 inhibitor 들을 drug screening을 통해 선별하였고, 그 중 NF-kB signaling 의 inhibition이 axin 과 b-catenin expression 의 감소와 관련되어 있고, cell viability 도 효과적으로 감소시켰다. NF-kB signaling을 inhibition 하는 inhibitor 들 중에서, Bay11-7082 (Bay) 가 가장 효과적이었다. 다른 analysis 들을 통해 NF-kB signaling inhibitor 들이 아닌 Bay11-7082 를 처리했을 때, axin와 b-catenin 그리고 GSK3b 을 더욱 효과적으로 proteosomal degradation 시켰고, Wnt signaling activity를 감소 시킬 수 있다는 Bay11-7082 의 다른 effect 을 확인할 수 있었다. Bay11-7082 의 additional effect 는 AGS cell 과 같이 Wnt activity 가 높은 cell 에서 더 효과적이다. EC96 cell 은 Wnt signaling 이 억제되어 있고 NF-kB signaling 이 증가되어 있어 axin와 b-catenin 그리고 GSK3b 의 proteasomal degradation 을 보이지 않는다. 그럼에도 불구하고, Bay11-7082 는 AGS 와 EC96 의 cell viability 를 감소시킨다. 게다가 axin expressing HeLa (HeLa-axin) 은 XAV939 가 아닌 Bay11-7082 처리에 의해 cell viability 가 감소되었고, 이는 axin expressing cell 에서 Bay11-7082 의 효과적인 영향을 보여주었다. 따라서 이러한 결과들은 Bay11-7082 가 XAV939 resistant cancer cell을 위한 anti-cancer agent 의 효과적인 예가 될 수 있음을 시사한다. | - |
dc.description.tableofcontents | Ⅰ. Introduction 5 Ⅱ. Materials and Methods 15 1. Cell culture 15 2. Antibodies 15 3. Cell counting with Hemocytometer 15 4. Cell Proliferation assay 16 5. Immunoblot analysis 16 6. Nuclear/Cytoplasmic Fraction 17 7. Immunofluorescence analysis 17 8. Statistical analysis 18 Ⅲ. Results 19 1. Inhibition of NF-kB signaling effectively reduces cancer cell viability 19 2. Triptolide, Celastrol, and Bay11-7082 inhibits NF-kB nuclear translocation 21 3. Bay11-7082 reduces axin and β-catenin expression in HeLa, HeLa-XAV and HeLa-axin cells 23 4. Bay11-7082 induces proteasomal degradation of axin and β-catenin 25 5. Bay11-7082-induced proteasomal degradation is not associated with GSK3β activity 27 6. NF-kB signaling inhibition and proteasomal degradation are separate pharmacological effects of Bay11-7082 29 7. Bay11-7082 is effective anti-cancer agent for cancer cells, including XAV939-resistant cells 34 Ⅳ. Discussion 36 Ⅴ. References 47 Ⅵ. Abstract (in Korean) 67 | - |
dc.format | application/pdf | - |
dc.format.extent | 943975 bytes | - |
dc.language | eng | - |
dc.publisher | 이화여자대학교 대학원 | - |
dc.subject.ddc | 600 | - |
dc.title | Study of the anti-cancer effect and mechanism of NF-κB inhibitor, Bay11-7082 | - |
dc.type | Master's Thesis | - |
dc.format.page | 67 p. | - |
dc.identifier.thesisdegree | Master | - |
dc.identifier.major | 대학원 바이오융합과학과 | - |
dc.date.awarded | 2019. 2 | - |