請用此 Handle URI 來引用此文件: http://hdl.handle.net/11455/20163
標題: Cisplatin transiently up-regulates hHR23 expression through enhanced translational efficiency in mammalian cells
作者: 沈玉涵
Shen, Yu-Han
關鍵字: Rad23
DNA repair
出版社: 生物醫學研究所
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摘要: DNA damage agents are common therapeutic drugs to cancers. Unfortunately, DNA repair systems induced by anti-cancer drugs seem to play a key role in mediating drug resistance in cancer treatment. To evaluate the expression of DNA repair enzymes upon cancer treatment, lung adenocarcinoma cell line A549 was challenged with DNA damage agent, cisplatin. Cisplatin enhanced hHR23, an accessory protein involved in nucleotide-excision repair (NER) at early lesion-recognition step, protein expression with the dose-dependent and time-dependent manners. Low-dose cisplatin significantly induced hHR23 expression accompanied by the increased protein levels of p53, p21, and XPC. U0126 and LY294002 treatment attenuated hHR23 expression induced by cisplatin, indicating the MEK/ERK and PI3K/AKT signaling pathways were involved in the process. The mechanism underlying the MEK/ERK signaling on hHR23 protein expression relied on the increased translational initiation through the phosphorylation of eIF-4B. Moreover, knock-down of hHR23B by RNA interference decreased the repair of cisplatin-mediated DNA damage, cell survival, p53 and XPC induction. In contrast, overexpression of hHR23B enhanced the repair activity towards cisplatin-damaged DNA. Altogether, these results speculated that increased hHR23 by cisplatin is regulated by proliferative signaling pathways. Since cisplatin-induced DNA damage is mainly repaired by homologous recombination (HR) and NER, the role of hHR23B in HR pathway will be further investigated. In sum, the status of HR23 protein induction may be important in assessing patient prognosis in the clinical setting.
目前很多癌症藥物常藉由傷害細胞的DNA當作毒殺癌細胞的手段,但是癌症患者往往在化療藥物的療程中產生癌細胞抗藥性,使癌細胞不再受到藥物處理致死,其中一種原因是癌細胞會促進DNA修復系統的運作,使癌細胞在短時間內修復受損的DNA而免於死亡。 為了證實在癌症藥物治療時DNA修復酵素的表現程度,我們選用肺腺癌細胞株A549來處理一種傷害DNA的藥物”順鉑”,進一步的觀察到參與在早期核苷酸切除修復(Nucleotide excision repair, NER)步驟的hHR23/RAD23蛋白質表現程度隨著順鉑的劑量以及處理時間增加而增加。 低劑量的順鉑除了促進細胞中hHR23蛋白質的表現量之外也會增加p53、p21、和XPC的蛋白質的表現。 利用U0126與LY294002分別抑制MEK/ERK和PI3K/AKT訊息傳遞路徑,會減少順鉑所誘導的hHR23蛋白質表現。 另外,轉錄起使因子eIF-4B的聯酸化活化增加轉錄效率,促進MEK/ERK訊息路徑所調控的hHR23蛋白質表現。 重要的是利用RNA干擾技術靜默hHR23後處理順鉑會減少DNA修復能力、細胞存活率以及p53和XPC蛋白質的表現量,相反的,過度表現hHR23蛋白質會提升被順鉑傷害DNA之修補能力。 總結來說,我們看到順鉑藉由增加訊號傳遞路徑而誘導hHR23蛋白質表現,所以期許可以在臨床癌症病人做藥物治療時,藉由觀察hHR23蛋白質表現量來進行其癒後狀況的評估。 由於順鉑所引發的DNA傷害主要經由同源互換(homologous recombination ,HR)和核苷酸切除修復,所以接下來我們要進一步探討在同源互換中hHR23B蛋白質扮演的角色。
URI: http://hdl.handle.net/11455/20163
其他識別: U0005-0308201115581300
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-0308201115581300


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