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  • 學位論文

抑制大腸直腸癌細胞株SW620增生之植化素對丙酮酸激酶M2之調控

Influence of anti-colorectal cancer phytochemicals on Pyruvate Kinase M2 in SW620 cell line

指導教授 : 蔣丙煌

摘要


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。

並列摘要


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.

參考文獻


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