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標題: | 新穎性第六亞型組蛋白去乙醯酶抑制劑在膠質母細胞瘤之抗癌作用機轉探討 Investigation of the anticancer mechanisms of a novel HDAC6 inhibitor in glioblastoma |
作者: | 劉佳蓉 Jia-Rong Liu |
指導教授: | 陳基旺 Ji-Wang Chern |
關鍵字: | 膠質母細胞瘤,第六亞型組蛋白去乙醯?,細胞自噬,抗癌免疫力,蛋白水解, glioblastoma,HDAC6,autophagy,anticancer immunity,proteolysis, |
出版年 : | 2018 |
學位: | 博士 |
摘要: | 膠質母細胞瘤是惡性腦癌中最致命、也是復發性最高的癌症。目前對膠質母細胞瘤的治療主要有手術切除,放射線治療及合併使用化療藥物治療等方式。但這些治療只能延緩病患平均存活率約六個月,無法有效治癒。因此,開發更有效的抗腦癌藥物及治療策略有其迫切的需求。研究指出,第六亞型組蛋白去乙醯酶(HDAC6)在膠質母細胞瘤中有異常地過度表達,而且若藉由siRNA誘導的HDAC6 基因敲除來減少HDAC6的蛋白量可以有效抑制膠質母細胞瘤的增殖。在本論文中,我們證實在實驗室中新合成出來的高選擇性HDAC6抑制劑,J22352,它可以促使在膠質母細胞瘤細胞中異常過度表達的HDAC6蛋白水解,顯著減少HDAC6蛋白的表現量,進而減少癌細胞轉移,抑制癌細胞的自噬能力,達到顯著的腫瘤生長抑制。在動物實驗中,有90%腫瘤生長抑制率。值得注意的是,J22352更降低了PD-L1的免疫抑制活性,增加抗癌免疫反應的T細胞活性。總而言之,這些實驗結果表明J22352可以有效促進HDAC6蛋白降解,同時藉由抑制細胞自噬效果並增加T細胞的抗癌免疫反應來達到抗癌作用。 Glioblastoma is the most fatal type of primary brain cancer, and current treatments for glioblastoma are insufficient. HDAC6 is overexpressed in glioblastoma, and siRNA-mediated knockdown of HDAC6 inhibits glioma cell proliferation. Herein, we report a high-selective HDAC6 inhibitor, J22352, which decreased the abundance of overexpressed HDAC6 in glioblastoma. The consequences of decreased HDAC6 expression in response to J22352 inhibited cell migration, increased autophagic cancer cell death and significant tumor growth inhibition in xenograft mouse model. Notably, J22352 reduced the immunosuppressive activity of PD-L1, leading to the restoration of host anti-tumor activity such as increased levels of CD8+ T cells, interferon-gamma (IFN-γ) and tumor-associated inflammatory cytokines IL-2 as well as reduced levels of IL-6. Taken together, these results demonstrate that J22352 can significantly target glioblastoma by not only inhibiting autophagy associated with enhanced anticancer immunity but also evoking PROTAC-like proteolytic degradation of HDAC6. Therefore, this highly selective HDAC6 inhibitor can be considered a potential therapeutic for the treatment of glioblastoma and provide an insight into the mechanisms of this therapy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77656 |
DOI: | 10.6342/NTU201800889 |
全文授權: | 未授權 |
顯示於系所單位: | 藥學系 |
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