探討六碳糖激酶第II型對攝護腺癌細胞其生理上的調控機制

Physiological Role of Hexokinase II in Regulating Prostate Cancer Progression

王郁婷(Yu-Ting Wang)

指導教授 ： 李佳陽

高雄醫學大學/醫學院/醫學系基因體學科碩士班/碩士(2016年)

摘要

攝護腺癌是美國最常見的癌症，在美國男性的癌症死因中排名第二，在國人十大癌症死因中，則排名第六，雖然比西方國家低得多，但卻有逐年增高的趨勢。攝護腺癌容易復發與轉移，常用的荷爾蒙治療平均三至五年後，會再度復發成為雄激素非依賴型攝護腺癌，對於雄激素非依賴型的攝護腺癌，目前仍無有效的治療方式。因此，開發新的治療方式是刻不容緩的事情。
高度依賴葡萄糖代謝是癌細胞的特性之一，有別於正常細胞依賴粒線體氧化磷酸化過程提供ATP來給予細胞活動所需之能量，癌細胞偏好利用有氧糖解作用取得能量，這種特性即稱為瓦伯效應。糖解作用的增加與攝護腺癌細胞發展及侵入性有關。六碳糖激酶是参與糖解作用步驟中的第一個不可逆反應的酵素，其作用在將葡萄糖磷酸化變成6-磷酸葡萄糖。目前已知有4種不同型態的六碳糖激酶，分別為I、II、III及IV型。先前的研究指出，癌細胞高度表現六碳糖激酶第II型（Hexokinase II；HK-II），並證實HK-II是癌細胞糖解作用重要的媒介酵素，其與腫瘤的生長有密切的關係，過度表現HK-II與惡性腦癌病人的預後差以及存活率降低有關。然而，HK-II對攝護腺癌細胞的生長及其調控機制目前仍不清楚。
本研究的目的在探討HK-II對攝護腺癌細胞生長速率、化療藥物感受性及其調控機制，並希望可以透過高通量藥物篩選，找出HK-II的抑制劑。我們的研究結果顯示，降低細胞內HK-II表現會抑制攝護腺癌細胞生長速度、減少攝護腺癌細胞進行糖解作用，以及增加攝護腺癌細胞對化療藥物與放射線治療的敏感性。在機制方面，我們發現AKT-mTOR-MYC在調節HK-Ⅱ的在攝護腺癌細胞中的表達中扮演重要的角色。此外，我們找到可以抑制HK-II的化合物，截至目前為止，坊間仍無有效抑制HK-II的抑制劑可於癌症治療上，我們將進一步研究此化合物對於攝護腺癌的調控機轉以及進行動物實驗測試對攝護腺癌生長之影響，期望未來能開發出針對抑制HK-II的有效抑制劑，用於癌症治療上。

關鍵字

攝護腺癌 ； 瓦伯效應 ； 六碳糖激酶第II型 ； AKT ； mTOR ； c-MYC

並列摘要

Prostate cancer is the most common cancer and the second leading cause of cancer death in United States. In Taiwan, although the incidence and mortality rates of prostate cancer are much lower than the Western countries, these rates have been rising rapidly in the past decade. Most tumor cells exhibit a different metabolic pattern than normal differentiated cells. In contrast to normal differentiated cells that rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells preferentially use aerobic glycolysis over mitochondrial oxidative phosphorylation for glucose-dependent ATP production, known as “Warburg effect”. Increased glycolytic phenotype is associated with prostate cancer progression and aggressiveness. The first irreversible reaction of glycolysis is catalyzed by hexokinase (HK), which phosphorylate glucose to glucose-6 phosphate. In mammals, there are four types of HK isoforms, HK-I, HK-II, HK-III, and HK-IV. Only HK-II is overexpressed in cancer cells and contributes to the high glycolytic rate in tumors. Thus, HK-II is regarded as a potential target for anticancer therapy. The aim of this study is to examine the role of HK-II in regulating the growth and progression of prostate cancer cells. Our results showed that knockdown of HK-II decreases the cell growth rate and enhances both chemo-and radio-sensitivities of prostate cancer cells. For the mechanism of action of HK-II, our results demonstrated that the AKT-mTOR-MYC plays an important role in regulating the expression of HK-II in prostate cancer cells. In addition, we found a compound (compound 1) that inhibits the expression of HK-II in prostate cancer cells. Up to now, there is no effective HK-II inhibitor used in cancer therapy. We will further study the effect of compound 1 in regulating prostate cancer progression and develop a novel therapeutic agent in targeting HK-II-mediated aerobic glycolysis in cancer.

並列關鍵字

Prostate cancer ； Warburg effect ； Hexokinase II ； AKT ； mTOR ； c-MYC

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