系統識別號 U0026-3006201016071900
論文名稱(中文) 血癌細胞透過肝醣合成酶激酶-3beta增加Galectin-3表現逃脫凋亡刺激
論文名稱(英文) Escape of Leukemia Cells from Apoptotic Stimuli by Glycogen Synthase Kinase-3beta-regulated Galectin-3
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 98
學期 2
出版年 99
研究生(中文) 鄭怡琳
研究生(英文) Yi-Lin Cheng
學號 t3697409
學位類別 碩士
語文別 英文
論文頁數 76頁
口試委員 指導教授-張權發
中文關鍵字 Galectin-3  GSK-3β  細胞凋亡  促存活性Bcl-2家族蛋白  血癌 
英文關鍵字 Galectin-3  GSK-3β  apoptosis  pro-survival Bcl-2 family proteins  leukemia 
中文摘要 無論是絲氨酸/酥胺酸激酶之肝醣合成酶激酶-3β (GSK-3β) 或半乳糖苷結合凝集素-3 (Galectin-3),都可以調控癌細胞的生存及凋亡。然而,根據不同的細胞及刺激使得它們會有不同的角色。本研究中我們發現血癌細胞可透過GSK-3β及galectin-3的調控機制而逃脫凋亡刺激。慢性骨髓性血癌細胞株K562在給予順鉑(一種以鉑為基底的化療藥物) (Cisplatin)、神經鞘脂神經醯胺類似物C2-ceramide或磷脂醯肌醇-3激酶(PI3K)抑制劑LY294002的凋亡刺激下,蛋白質分析發現galectin-3會隨著時間透過轉錄作用而增加表現。特別的是galectin-3是在對死亡刺激缺乏感受性的細胞中增加。過量表現galectin-3可幫助細胞抵抗凋亡刺激,然而降低galectin-3表現則增加細胞對凋亡刺激的感受性。誘導表現的galectin-3在細胞中主要分布在粒線體。促存活性Bcl-2家族蛋白的表現(特別是Mcl-1) 在凋亡刺激下會減少,而此現象在過量表現galectin-3後會被抑制,但在減少galectin-3表現後則會增強。在凋亡刺激之下隨著Akt的去活化導致GSK-3β會活化,而在透過藥理的方式及short hairpin RNA方式抑制GSK-3β後則會抑制galectin-3表現並增加凋亡程度以及減少細胞群落的形成,這也代表刺激活化的GSK-3β具有促細胞存活的角色。根據本研究的結果,我們發現GSK-3β會媒介galectin-3的表現進而穩定抗凋亡Bcl-2家族蛋白的表現,而此機制對於血癌細胞逃脫凋亡刺激是非常重要的。以GSK-3β及galectin-3作為標靶治療將可提高現行抗癌藥物如cisplatin的抗血癌效果,以避免抗藥性血癌的發生。
英文摘要 Either serine/threonine kinase glycogen synthase kinas (GSK)-3β or galectin-3, a β-galactoside-binding lectin, is regulated for cancer cell survival and apoptosis depending upon the cell type and stimulus. We investigated a GSK-3β-regulated and galectin-3-mediated mechanism used by leukemia cells to escape from apoptotic stimuli. Galectin-3 expression was time- and transcription-dependently deregulated in K562 chronic myeloid leukemia cells stimulated for apoptosis by cisplatin (a platinum-based chemotherapy drug), sphingolipid ceramide analog C2- ceramide, and LY294002 (a phosphatidylinositol 3-kinase inhibitor). Notably, galectin-3 was upregulated in insusceptible cells, which were resistant to apoptosis. Forced galectin-3 expression caused resistance to apoptosis, whereas knockdown galectin-3 expression increased susceptibility to apoptosis. Sub-cellular distribution of inducible galectin-3 was mitochondria-specific. Apoptotic stimuli decreased pro-survival Bcl-2 family protein expression (especially Mcl-1), whereas galectin-3 overexpression reversed but it was enhanced by a galectin-3 expression knockdown. Under apoptotic stimulation, GSK-3β was activated after Akt was inactivated and GSK-3β was inhibited—either pharmacologically or using short hairpin RNA to abolish galectin-3, increase apoptosis, and inhibit colony formation—which suggests a pro-survival role for GSK-3β. We found that GSK-3β upregulated galectin-3 and stabilized anti-apoptotic Bcl-2 family proteins, which is important for the escape of leukemia cells from apoptotic stimuli. Targeting GSK-3β and galectin-3 enhanced the effect of traditional anticancer drugs, such as cisplatin to prevent development of drug resistance in leukemia.
論文目次 Abstract in Chinese 1
Abstract in English 2
Acknowledgement 3
Abbreviations 4
Contents 7
List of Figures 10
I Introduction 12
I-1 Drug resistance in leukemia 12
I-2 Apoptotic stimuli 12
I-3 Galectins 13
I-4 The role of Galectin-3 in tumorigenesis 14
I-5 The role of Galectin-3 in apoptosis 14
I-6 The role of GSK-3β in apoptosis 15
I-7 The apoptotic role of GSK-3β in leukemia 16
II Study Objective and Specific Aims 18
II-1 Objective 18
II-2 Specific aims 18
II-3 Study Flow Chart 18
III Materials and Methods 20
III-1 Cell cultures and reagents 20
III-2 Western blot analysis 20
III-3 Analyzing cell apoptosis 21
III-4 Immunostaining 22
III-5 Plasmid transfection 22
III-6 Lentiviral-based short hairpin RNA 22
III-7 Colony forming assay 23
III-8 Total RNA extraction and RT-PCR 23
III-9 Statistical analysis 24
IV Results 25
IV-1 Apoptotic stimuli transcription-dependently induce galectin-3 expression in K562 chronic myeloid leukemia cells 25
IV-2 Inducible galectin-3 is important for the survival of apoptotically stimulated cells 25
IV-3 Inducible galectin-3 is highly expressed in apoptotically stimulated mitochondria 26
IV-4 Inducible galectin-3 stabilizes apoptotically stimulated Mcl-1, Bcl-xL, and Bcl-2 26
IV-5 Activation of GSK-3β is essential for inducible galectin-3 expression and survival in apoptotically stimulated cells. 27
IV-6 GSK-3β participates in galectin-3 expression, in part, through transcriptional regulation 28
IV-7 GSK-3β and galectin-3 are critical for the survival of apoptotically stimulated cells 28
V Discussion 30
V-1 The brief summary of the study 30
V-2 The role of inducible galectin-3 in apoptosis 30
V-3 The anti-apoptotic mechanisms of inducible galectin-3 31
V-4 The molecular mechanism of galectin-3 expression regulated by GSK-3β 32
V-5 The relationship between Mcl-1 and GSK-3β 32
VI Conclusion 34
References 35
Figures and Figure Legends 44
Appendix 59
A Materials 59
A-1 Chemicals 59
A-2 Antibodies 61
A-3 Kits 62
A-4 Consumables 62
A-5 Apparatus 62
B Methods 63
B-1 Cell Culture 63
B-1.1 Cell Culture Medium 63
B-1.2 Cell Passage 64
B-1.3 Cell Freeze 64
B-1.4 Cell Defreeze 64
B-2 Western Blot 64
B-2.1 Lysis buffer 64
B-2.2 5× loading dye and TBS-T 65
B-2.3 Running gel preparation 65
B-2.4 Stacking gel preparation 66
B-2.5 Cell lysate preparation 66
B-2.6 SDS-PAGE 66
B-3 Immunocytochemistry 67
B-4 PI staining 67
B-5 RT-PCR 67
B-5.1RNA extraction 67
B-5.2 RT 68
B-5.3 PCR 68
B-6 Lentiviral-based shRNA knockdown 69
B-6.1 Plasmid preparation 69
B-6.2 Lentiviral production 69
B-6.3 Lentiviral concentration 71
B-6.4 Lentiviral infection 71
B-7 Overexpression 72
B-7.1 Cloning 72
B-7.1 Plasmid transfection 73
B-8 Colony forming assay 73

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