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系統識別號 U0026-2307201517015400
論文名稱(中文) Rigosertib藥物造成瀰漫性大B細胞淋巴瘤細胞死亡的調控機制
論文名稱(英文) The regulatory mechanism of cell death by rigosertib in diffuse large B-cell lymphoma (DLBCL)
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 戴憶涵
研究生(英文) Yi-Han Dai
學號 S96021066
學位類別 碩士
語文別 英文
論文頁數 53頁
口試委員 指導教授-張孔昭
口試委員-陳立宗
口試委員-陳彩雲
口試委員-謝奇璋
中文關鍵字 瀰漫性大B細胞淋巴瘤  類小泛素化蛋白  c-Myb  TRAF6  Rigosertib 
英文關鍵字 DLBCL (diffuse large B-cell lymphoma)  c-Myb  SUMO1  Rigosertib  TRAF6 
學科別分類
中文摘要 瀰漫性大B細胞淋巴瘤屬非何傑金氏淋巴瘤中最普遍且具侵略性的的類別,其中約30%患者對於後續的治療並無效果或伴隨產生抗性,甚至達半數的病患無法承受高劑量的傳統化學治療。先前的研究指出多重激酶抑制劑Rigosertib能選擇性的毒殺瀰漫性大B細胞淋巴瘤細胞而不毒害非增生性淋巴母細胞。Rigosertib將誘導瀰漫性大B細胞淋巴瘤細胞株中RanGAP1高度磷酸化與類小泛素化,而類小泛素化對於核質中蛋白的運輸與轉錄基因的活性抑制扮演著重要的角色。Rigosertib能使多數腫瘤細胞株死亡,然而在瀰漫性大B細胞淋巴瘤細胞中確切的死亡機制途徑仍尚未明瞭。因此本篇目標將於體外與體內分析Rigosertib的藥效並進一步探討其在腫瘤生物分子層面的影響。首先, 利用MTT(CCK-8)分析去偵測Rigosertib藥物處理過後非增生性淋巴母細胞以及瀰漫性大B細胞淋巴瘤細胞株的細胞存活率,結果發現Rigosertib具選擇性毒殺且極具潛能能發展成瀰漫性大B細胞淋巴瘤的標靶藥物;有趣的是, 利用核質分離分析上發現,經Rigosertib處理過後能抑制RanGAP1 / TRAF6 / c-Myb這些被類小泛素化的蛋白質入核表現;並且進一步透過免疫共沉澱分析發現被類小泛素化的RanGAP1 / TRAF6 / c-Myb蛋白質間的交互關係。本篇研究中,結果顯示Rigosertib經 RanGAP1*SUMO1途徑中Ubc9引起的類小泛素化作用而牽曳c-Myb蛋白使坐落於細胞質中,最終達到抑制c-Myb蛋白的表現活性,因此我們認為Rigosertib是極具潛能可發展成治療瀰漫性大B細胞淋巴瘤的藥物。專一性地抑制c-Myb和TRAF6蛋白表現將引起細胞凋亡並造成細胞週期受阻。因為在其他惡性腫瘤中c-Myb和TRAF6蛋白表現異常,因此未來在臨床的治療應用上, c-Myb或是TRAF6將是一個廣泛且可行的治療目標。綜合以上結果,這些研究資料結果能支持Rigosertib未來應用在治療瀰漫性大B細胞淋巴瘤的臨床藥物發展。
英文摘要 Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, shows either no response or development of resistance to further treatment in 30% patients. Even approximately half of patients are not eligible for high-dose chemotherapy. Previous studies report that rigosertib (ON 01910.Na), a multi-kinase inhibitor is selectively cytotoxic for DLBCL and induces more hyperphosphorylation and sumoylation of RanGAP1 in DLBCL cells than in non-neoplastic lymphoblastoid cell line (LCL). Sumoylation is linked to nucleocytoplasmic transport and transcriptional gene repression. The exact mechanism of rigosertib-induced cell death in DLBCL remains unclear. Our aim was to analyze the efficacy of rigosertib against DLBCL cells in vitro and in vivo and its molecular effects on tumor biology. First, LCL and DLBCL cells were treated with rigosertib and their viabilities were assessed by the MTT assay. We found that rigosertib was selectively cytotoxic and had potential for targeting DLBCL. Interestingly, rigosertib inhibited nuclear entry of sumoylated proteins RanGAP1, TRAF6 and C-Myb that was confirmed by immunofluoresence. Moreover, co-immunoprecipitation identified that rigosertib sequestered c-Myb and TRAF6 in the cytoplasm by stimulating their sumoylation through the RanGAP1*SUMO1*Ubc9 pathway. Specific knockdown of C-Myb and TRAF6 induced apoptosis and cell cycle arrest. Xenograft mice bearing lymphoma cells also exhibited effective tumor regression on rigosertib treatment. Thus, suppression of c-Myb and TRAF6 activity may be the potential therapeutic targets in DLBCL. These data support the clinical development of rigosertib in DLBCL.
論文目次 Abstract ii
中文摘要 iv
誌謝 v
Abbreviations 1
Introduction 2
Diffuse large B-cell lymphoma (DLBCL) 2
Treatment of DLBCL 3
Study of rigosertib (ON 01910.Na) in cancers 5
Mechanisms of Rigosertib (ON 01910.Na) for cancer therapy 6
Materials and Methods 9
Culturing DLBCL and B-lymphoblastoid cell lines 9
Assessment of rigosertib (ON 01910.Na) cytotoxic effects on DLBCL and B-LCL 9
Subcellular fractionation of DLBCL and LCL 10
Co-immunoprecipitation 10
Immunoblotting assay 11
Immunofluorescence (IF) staining 11
Transfecting C-Myb and TRAF6-specific shRNA into DLBCL cell lines 12
Immunohistochemistry (IHC) staining 12
Cell death and cell cycle assays by flow cytometry 13
Xenograft mouse model of lymphoma 14
Statistical analysis 14
Results 16
Rigosertib (ON 01910.Na) induced more cell death in DLBCL cell lines (HT & SU-DHL5) but mild effects on non-neoplastic LCL 16
Rigosertib induced hyperphosphorylation of RanGAP1 with increased expression of RanGAP1*SUMO1 but decreased expression of TRAF6 and c-Myb in DLBCL cell lines 16
Expression of SUMO1-modified RanGAP1 / TRAF6 / c-Myb was suppressed in nucleus but accumulated in cytoplasm after ON 01910.Na treatment 16
RanGAP1*SUMO1*Ubc9 complex promoted accumulation of sumoylated c-Myb/TRAF6 complex in cytoplasm by ON 01910.Na treatment 17
C-Myb or TRAF6 depletion caused cell cycle arrest at the G0/G1 phase and cell death 17
ON 01910.Na effectively reduced the tumor growth in DLBCL-bearing NOD/SCID mice 18
Discussion 19
References 23
Figures and Tables 28
Figure 1. ON 01910.Na induces more cell death in DLBCL cell lines (HT&SU-DHL5). 28
Figure 2. ON 01910.Na induces hyperphosphorylation of RanGAP1 with increased expression of RanGAP1*SUMO1 but decreased expression of TRAF6 and C-myb at higher dosage. 30
Figure 3. Expression of sumoylated RanGAP1, TRAF6 and C-myb is decreased in nucleus but increased in cytoplasm after ON 01910.Na treatment. 32
Figure 4. Immunofluorescence staining reveals that RanGAP1, TRAF6 and C-myb are co-localized. Besides, the expression of RanGAP1, TRAF6 and C-myb modified with SUMO1 is decreased in nucleus and retained in cytoplasm at 0.5 μM of ON 01910.Na. 36
Figure 5. Immunoblotting analysis of c-Myb and its interaction with Ubc9 and TRAF6 modified by SUMO1 in DLBCL cells. 40
Figure 6. Knockdown of C-myb reduces viability, induces apoptosis and causes the cell cycle arrest in the G0/G1 phase in DLBCL (HT & SU-DHL5) cells. 42
Figure 7. Depletion of TRAF6 induces DLBCL (HT & SU-DHL5) cell apoptosis. 44
Figure 8. ON 01910.Na effectively reduces the tumor growth in lymphoma bearing NOD/SCID mice. 45
Figure 9. Hypothetical model for the regulatory mechanism of cell death by rigosertib in DLBCL (modified from ref (39)). 46
Table1 Antibodies of immunoblot 47
Table2 ShRNA clones from RNAi core 48
Table3 Characterization of DLBCL cell lines from DSMZ 49
Appendix 50
Appendix 1. 50
Appendix 2-1. 51
Appendix 2-2. 51
Appendix 3. 52
Appendix 4-1. 53
Appendix 4-2. 53


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