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標題: 植物成分deoxyelephantopin與化療藥紫杉醇作用於乳腺癌細胞之分子標的與機制研究
Novel molecular targets and mechanisms of phytoagent deoxyelephantopin and chemotherapeutic drug paclitaxel against mammary carcinoma cell
作者: 李慧玲
Lee, Wai-Leng
關鍵字: 倍半萜類;pharmacological action;傳統藥草;地膽草;紫杉醇;乳腺腫瘤;活性氧化物;中心體;泛素;上皮生長因子;細胞運動;微管蛋白質;骨架蛋白質;鈣蛋白酵素;肌動蛋白;細胞凋亡;內質網;二維凝膠電泳;蛋白酶體;蛋白質體;轉移;藥理作用機制;乳癌治療;cell motility;reactive oxygen species;ubiquitinated proteins;centrosomal aggregates;epithelial growth factor;calpain;cytoskeletal protein;actin;proteomic study;proteasomal proteolysis;apoptosis;endoplasmic reticulum stress;proteasome;MetaCore database;two-dimensional differential in-gel electrophoresis;breast cancer treatment;traditional medicinal herb;Elephantopus scaber;germacranolide sesquiterpene lactone;deoxyelephantopin;paclitaxel;TS/A cells;mammary adenocarcinoma;metastasis
出版社: 生物科技學研究所
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越來越多研究指出植物衍生而來的化合物具有化學預防或化學治療的特性,並具有潛能結合現有的化學療法來有效的治療各種癌症。從傳統藥草菊科植物地膽草 (Elephantopus scaber L.) 所萃取出具有抗癌性質的活性成分,主要是屬於倍半萜類 (germacranolid sesquiterpene lactone) 的deoxyelephantopin (DET)。相較於常被使用來治療乳癌的化療藥物紫杉醇 (paclitaxel, PTX),我們實驗室先前的研究證實不論是在活體外 (in vitro) 或活體內 (in vivo) 的實驗系統下,DET的處理可以更有效的抑制老鼠TS/A乳腺腫瘤的生長與轉移。本論文研究主要利用蛋白質體技術也就是二維凝膠電泳及液相層析-電熱灑離子化二次質譜儀 (liquid chromatography electrospray ionization tandem mass spectrometry, LC-ESI-MS/MS) 來分析TS/A細胞中蛋白質在DET 和PTX的處理下表現的差異,然後利用生物資訊軟體MetaCore來分析顯示差異的蛋白之間的相互關係以及有關的生物訊息途徑。實驗結果顯示,DET和PTX對涉及蛋白質降解及鈣離子傳送的蛋白質有顯著的影響,從而推斷出這兩種化合物可能會影響TS/A細胞中蛋白酶體 (proteasome) 及內質網的功能。利用西方墨點法進一步證實,DET和PTX的處理同樣會引起內質網的壓力 (ER stress) 繼而導致細胞凋亡,而只有DET可以抑制TS/A細胞蛋白酶體中蛋白質降解的功能。另一方面,蛋白質體研究的結果也顯示DET會影響TS/A細胞的肌動蛋白 (actin) 系統,同時抑制鈣蛋白酵素 (calpain) 對多種骨架蛋白質的水解,而PTX主要是影響細胞內微管蛋白質系統。在更深入的實驗中發現DET會影響鈣蛋白酵素的催化活性及其所調控的細胞運動形態。MetaCore分析的結果也顯示Rho GTPase可能涉及DET對肌動蛋白的作用,而DET對TS/A細胞的處理確實明顯的抑制了由上皮生長因子 (EGF) 活化的Rac 1蛋白及其下游的層狀偽足 (lamellipodia) 的形成。另外,DET會阻擾上皮生長因子在TS/A細胞中的運輸及導致被泛素修飾的蛋白 (ubiquitinated proteins) 聚集在中心體所在處。值得注意的是,DET所誘導產生的活性氧化物 (ROS) 是引發中心體聚集物的上游刺激分子,進而可能造成限制乳癌細胞的活性及移動能力。綜合以上結果,本篇論文之研究提供深入證據闡明DET抑制乳腺癌細胞的活性與轉移的新穎藥理作用機制。

Accumulating evidences have shown that various plant-derived phytocompounds possess chemopreventive or chemotherapeutic properties, suggesting their potential for use in combination with chemotherapeutics as effective treatments for various cancers. One such potent antitumor phytocompound is the major germacranolide sesquiterpene lactone, deoxyelephantopin (DET) from the traditional medicinal herb Elephantopus scaber L (Asteraceae). Previously, DET was found in our lab to suppress mammary carcinoma metastasis in vitro and in vivo with a more superior effect than Paclitaxel (PTX), a front line chemotherapeutic agent commonly utilized in the treatment of breast cancer. In this study, two-dimensional differential in-gel electrophoresis (2-D DIGE) and liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) were first used to profile proteins differentially expressed in TS/A cells, and affected functional protein networks were analyzed using MetaCore database. DET and PTX treatment resulted in regulation of molecules involved in proteolysis and calcium ion transport, suggesting the possible effects of both chemicals on proteasome and endoplasmic reticulum (ER) machinery in TS/A cells. Western blot analysis of marker proteins further verified that induction of ER stress was associated with apoptosis induced by both DET and PTX, but only DET inhibited proteasomal proteolysis in TS/A cells. Besides, proteomic study also suggested that DET affects actin cytoskeletal protein networks and downregulates calpain proteolyzed fragments of several actin-associated proteins, while PTX interferes mainly with microtubule proteins. Further investigation of the putative inhibitory effect of DET on calpain and associated cytoskeletal regulation found that DET inhibits enzymatic activity of calpain in TS/A cells. As Rho GTPases were suggested as part of DET action by MetaCore network analysis, epithelial growth factor (EGF)-mediated activation of Rac1 and formation of lamellipodia in TS/A cells were indeed remarkably suppressed by DET treatment. Further, DET impaired vesicular trafficking of EGF and induced formation of centrosomal aggregates of ubiquitinated proteins in TS/A cells. Notably, DET-induced reactive oxygen species (ROS) was observed to be the trigger for inducing the centrosomal ubiquitinated protein aggregates that might subsequently restrict cancer cell viability and motility. Together, this study provides novel mechanistic insights into the pharmacological action of DET against metastatic mammary cell migration.
其他識別: U0005-2507201122485600
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