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標題: | 探討BTK抑制劑BI1對前列腺癌細胞的移動力及型態之影響 The effect of BTK inhibitor BI1 on prostate cancer motility and cell morphology |
作者: | Yu-Kuang Fan 范有光 |
指導教授: | 李明學(Ming-Shyue Lee) |
關鍵字: | BI1,L-plastin,前列腺癌,侵襲能力,偽足, BI1,L-plastin,prostate cancer,invasion,pseudopodia, |
出版年 : | 2021 |
學位: | 碩士 |
摘要: | 標靶治療為針對病人臨床病徵、基因定序及疾病的致病機制做治療的醫療策略,而在此當中標靶藥物的專一性尤為重要,若標靶藥物有其他非主目標之標的則會影響其治療效率、藥物毒性以及副作用,因此瞭解完整的藥物標的可以進一步理解藥物的作用機制及使用時機。在實驗室先前的研究當中,我們發現Bruton kinase (BTK) inhibitor (BI1) 可作用於非原標靶蛋白之細胞骨架蛋白L-plastin,並抑制其功能。在前列腺癌細胞CWR22Rv1當中表現L-plastin蛋白可以增強其侵襲能力,而此一增強可以被BI1作用後抑制。此外,L-plastin的束肌絲(actin bundle)功能也可以被BI1降低。這些結果都顯示了BI1對L-plastin的抑制性,但其作用機制尚不明確。在本論文當中,我們使用了點突變及免疫沉澱法發現了BI1的作用於L-plastin第101個胺基酸半胱胺酸(Cys)並形成共價鍵結合,而在表現了L-plastin並增強侵襲能力的前列腺癌細胞中,若將表現的L-plastin第101號位點突變成絲氨酸(Ser)會使細胞的侵襲能力不再被BI1影響。在束肌絲實驗中,若使用101號位點突變的L-plastin重組蛋白進行實驗,可以發現BI1也不再能夠降低其功能。另一方面,在BI1的作用之下,在免疫螢光染色下可以發現前列腺癌細胞的偽足生成明顯的降低,也與前項L-plastin功能被抑制的結果相符。結合先前論文對於L-plastin第101號位點為調控其功能的重要中樞這點,我們認為BI1對於L-plastin功能的影響非常大,並可以透過其影響癌細胞的侵襲與移動。這些結果證明了L-plastin為BI1的重要標的蛋白,而在各癌症當中表現量都升高的L-plastin也具有作為未來小分子藥物標的的潛力。 A targeted drug has been estimated to have at least 6.3 targets and implicated that each drug exhibits its target profiles. If the target profile of each drug and the detailed drug action on the disease treatment can be revealed, the information will provide a precision guideline for a correct use of a drug on the right group of patients and improve precision medicine. In our previous study, we found that Bruton kinase inhibitor BI1 had an additional target, L-plastin, which has an actin bundling activity. BI1 could decrease prostate cancer CWR22Rv1 cell invasion and inhibit the actin bundling activity of L-plastin. However, the mechanism how BI1 targeted L-plastin remained largely unknown. In this study, I found that BI1 could covalently bind to the amino acid residue of cysteine 101 in the regulation helix domain of L-plastin. Moreover, BI1 could reduce the formation of pseudopodia in prostate cancer PC3 cells and thus decrease the cell invasion capability. The results together indicate that BI1 can target to L-plastin via a covalent linkage on L-plastin’s amino acid residue of cysteine 101 and results in inhibition of L-plastin activity, pseudopodia formation and prostate cancer cell motility. Our findings further suggest that BI1 has a repurposing potential against prostate cancer. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74449 |
DOI: | 10.6342/NTU202100100 |
全文授權: | 有償授權 |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
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