臺灣博碩士論文加值系統

大腸直腸癌(Colorectal cancer；CRC)位居國人罹患惡性腫瘤之冠，且為發生率上升速度最快的癌症。近年研究顯示，丙酮酸激酶M2 (Pyruvate kinase M2；PKM2)為腫瘤中的主要PK形式，對癌症進程有莫大的貢獻。在細胞質中，PKM2利用調節PK活性影響代謝反應，高活性PKM2可滿足細胞對能量的需求，低活性PKM2可協助累積生合成所需的原料並避免氧化壓力造成的傷害，使癌細胞獲得良好的生存優勢；在細胞核中，PKM2亦可參與多個訊息傳遞路徑，調控致癌基因的表現。因此，PKM2可促進癌細胞的增生及惡化能力，甚至對CRC病患的預後及存活率皆有負面的影響。本研究以CRC細胞株SW620為研究平台，選取四種具抑制CRC潛力的植化素，包含薑黃素(Curcumin；C)、槲黃素(Quercetin；Q)、白藜蘆醇(Resveratrol；RV)及紫檀芪(Pterostilbene；P)，觀察植化素對PKM2的影響。研究結果顯示，四種植化素皆可有效抑制PKM2的總表現量，並對細胞內PKM2的分布情形有所影響。在PKM2總量方面，以Quercetin的抑制效果最好，達66%抑制率；其次是Resveratrol，達44%抑制率；Curcumin位居第三，抑制率達24%；Pterostilbene殿後，雖有抑制趨勢但未達顯著性差異。進一步分析上述植化素對PKM2上下游相關蛋白質之影響，推測四種植化素主要是經由調節c-Myc與 HIF-1α達到抑制PKM2的效果。另外，四種植化素還可有效降低細胞核內的PKM2量，進而減少下游目標蛋白MEK5的表現，影響細胞增生能力。綜合上述所示，植化素可以經由調節PKM2，在總量及細胞內的分布情形，達到抑制CRC細胞株增生的目的，對延緩癌症的進程應當有所幫助。

Colorectal cancer (CRC) is the most common cancer in Taiwan and the incidence of CRC was dramatically raised during the past few decades. Recent studies demonstrated that pyruvate kinase M2 (PKM2) is the predominant PK isoform in tumor and supports growth advantage in tumorigenesis. In the cytoplasm, high activity PKM2 helps to generate enough energy and low activity PKM2 satisfies the anabolic demands of macromolecular biosynthesis. In addition to well-established role in the metabolic reprogramming in the cytoplasm, PKM2 is also shown to participate in regulation of oncogene transcription in the nucleus. Furthermore, PKM2 would promote high proliferation rate and malignant grade in CRC development. Clinical studies also showed that the increased PKM2 expression is highly associated with poor prognosis and high risk death in CRC patient. Since there are many phytochemicals have been reported with anti-CRC properties, but their bioactivities on regulating PKM2 have not been sufficiently investigated. Thus, the objective of this study was to investigate the effects of four potential anti-CRC phytochemicals, including Curcumin, Quercetin, Resveratrol and Pterostilbene on PKM2 in human CRC cell SW620. The results showed that all of the four phytochemicals could effectively suppress the total PKM2 expression and regulate the distribution of intracellular PKM2. Quercetin is the most effective phytochemical, resulting in a 66% inhibition of the total PKM2 protein level, followed by Resveratrol which has 44% inhibition ability. The third place is Curcumin, it reduces 24% expression of PKM2. The last one is Pterostilbene which tends to down-regulate expression of PKM2 but without significant difference statistically. Moreover, the decrease of PKM2 protein expression due to the four phytochemicals treatments may via inhibition of the expression of c-Myc and HIF-1α. Our results also showed that the four phytochemicals have abilities to reduce the nuclear PKM2 level and thereby inhibit the expression of nuclear PKM2 downstream target protein MEK5. Consequently, phytochemicals may suppress the total PKM2 expression and regulate the distribution of intracellular PKM2 to inhibit CRC cell proliferation. It seems that the PKM2-mediated effect of phytochemicals on cancer progression can provide a new dimension to cancer treatment.

口試委員會審定書 i
誌謝 ii
中文摘要 v
ABSTRACT vi
目錄 vi
圖目錄 ixii
表目錄 xii

第一章、 文獻整理.........................................1
第一節、　大腸直腸癌 (Colorectal cancer, CRC)..............1
第1項 大腸直腸癌癌症進程與分期............................4
第2項 大腸直腸癌癌症基因致癌機轉...........................8
第二節、 腫瘤細胞中的代謝改變...............................14
第1項 丙酮酸激酶M2 (Pyruvate Kinase M2, PKM2) 簡介......17
第2項 丙酮酸激酶M2的生合成...............................19
第3項 丙酮酸激酶M2之細胞代謝優勢與癌症的關係................23
第4項 丙酮酸激酶M2在細胞核中的功能與癌症的關係..............30
第5項 丙酮酸激酶M2與大腸直腸癌的關係......................37
第三節、 植化素..........................................41
第1項 薑黃素(Curcumin)................................41
第2項 槲皮素(Quercetin)...............................42
第3項 白藜蘆醇(Resveratrol)...........................42
第4項 紫檀茋(Pterostilbene)...........................43

第二章、 研究目的與實驗架構................................44
第一節、 研究目的........................................44
第二節、 實驗架構........................................45
第三章、 實驗材料與方法...................................48
第一節、 實驗材料與儀器設備................................48
第1項 細胞株來源......................................48
第2項 藥品試劑........................................48
第3項 儀器設備........................................51
第二節、 實驗方法........................................52
第1項 細胞培養........................................52
第2項 樣品配製........................................53
第3項 細胞存活率分析...................................54
第4項 細胞質與細胞核之蛋白質萃取方法......................56
第5項 蛋白質萃取與定量..................................57
第6項 SDS-PAGE 電泳分析...............................59
第7項 西方點墨法 (Western blotting)....................62
第8項 統計分析 (Statistics analysis)..................63

第四章、 結果與討論.......................................64
第一節、 植化素C、Q、RV與P對人類大腸直腸癌SW620細胞株之存活率影響 .......................................................64
第1項 植化素處理SW620細胞株達48小時之MTT實驗結果...........65
第2項 以MTT與Trypan blue染色計數實驗探討IC20與IC50濃度的植化素處理SW620細胞達24及48小時之細胞存活率影響......................69
第二節、 利用西方點墨法探討植化素對CRC細胞株中PKM2、HIF-1α及c-Myc總表現量之影響..............................................74
第1項 Curcumin對PKM2、HIF-1α及c-Myc總蛋白質表現量之影響....75
第2項 Quercetin對PKM2、HIF-1α及c-Myc總蛋白質表現量之影響...79
第3項 Resveratrol對PKM2、HIF-1α及c-Myc總蛋白質表現量之影響..84
第4項 Pterostilbene對PKM2、HIF-1α及c-Myc總蛋白質表現量之影響. .........................................................88
第三節、 利用西方點墨法探討植化素對CRC細胞株中PKM2於細胞核和細胞質中蛋白質的含量變化，以及MEK5總蛋白質表現量之影響....................91
第1項 Curcumin對PKM2於細胞核和細胞質的蛋白量含量變化，以及MEK5總蛋白質表現量之影響............................................92
第2項 Quercetin對PKM2於細胞核和細胞質的蛋白量含量變化，以及MEK5總蛋白質表現量之影響...........................................96
第3項 Resveratrol對PKM2於細胞核和細胞質的蛋白量含量變化，以及MEK5總蛋白質表現量之影響........................................100
第4項 Pterostilbene對PKM2於細胞核和細胞質的蛋白量含量變化，以及MEK 5總蛋白質表現量之影響..................................105
第四節、 綜合討論.........................................108
第1項 植化素對PKM2總量的影響.............................108
第2項 植化素對細胞內PKM2分布情形的影響.....................110

第五章、 結論.............................................111

第六章、 參考文獻..........................................112

附錄(一) 相關研究..........................................128
第一節、 利用免疫螢光染色法證實EGF可誘導大腸直腸癌SW620細胞株之PKM2進入細胞核中................................................128
第1項 研究動機與目的.....................................128
第2項 材料與方法........................................128
第3項 結果與討論........................................130
附錄(二) 期刊格式..........................................132

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