索拉非尼在肝細胞癌的效用及其作用機轉之探討

The study of mechanism underlying sorafenib efficacy in hepatocellular carcinoma cells

黃柏喬(Po-Chiao Huang)

指導教授 ： 陳韻如

義守大學/醫學院/生物科技學系/碩士(2018年)

摘要

索拉非尼是一種小分子多重酪氨酸蛋白質激酶抑制劑，目前是用於治療肝癌晚期病患的核准藥物。其作用機轉主要是透過抑制Raf-MEK-ERK路徑來抑制癌細胞增生及抑制血管內皮生長因子受體等來抑制癌症血管新生作用，但其完整的抗癌機制尚未完全被了解。本論文的研究目的即為探討索拉非尼是否還有透過其他的機制來產生抗癌作用。由研究結果可知，索拉非尼對肝癌細胞的抗癌作用是細胞增殖抑制為主，細胞凋亡誘發為輔。進一步結果可知其可增加轉錄因子4 (ATF4) 蛋白質表現來促進其抑癌效果。其中的機制為索拉非尼可活化ATF4-SESN2-AMPK路徑來抑制細胞增殖; 另一方面，索拉非尼也可活化ATF4-CHOP之細胞凋亡路徑來增加CHOP下游的DR5、Wars、PUMA等基因的表現及累積ROS的生成進而誘發細胞凋亡。由以上結果可知，索拉非尼除了透過已知的作用機轉，也可藉由增加轉錄因子4 蛋白質表現來促進其抑癌效果。

關鍵字

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並列摘要

Sorafenib is a small molecule inhibitor of several tyrosine protein kinases and has been approved for treatment of advanced hepatocellular carcinoma (HCC). The underlying mechanism is to inhibit tumor cell proliferation through blockage of Raf-MEK-ERK pathway as well as to inhibit angiogenesis through blockage of vascular endothelial growth factor receptor activity. However, its comprehensive mechanism underlying anti-tumor activity is not yet completely understood. The motivation of this thesis is to investigate whether sorafenib has other mechanism than the above known ones. According to our results, we found that sorafenib had major effect on cell proliferation inhibition and minor effect on apoptosis induction. Further analysis revealed that sorafenib increased transcription factor 4 (ATF4) expression to exert its anti-tumor activity. The underlying mechanism was that sorafenib induced ATF4-SESN2-AMPK pathway to inhibit cell proliferation. On the other hand, sorafenib also induced ATF4-CHOP apoptotic pathway to increase expression of downstream effectors of CHOP, including DR5, Wars and PUMA as well as accumulation of ROS production. As a result, sorafenib induced cell apoptosis. Based on our results above, we knew that sorafenib could inctrease ATF4 expression to exert its anti-tumor activity in addition to the known mechanism.

並列關鍵字

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參考文獻

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