| 摘要: | 細胞缺乏養分或受氧化壓力時啟動autophagy, FOXO 及相關基因(autophagy related-genes, Atgs),使細胞胞器與溶?體(lysosome)融合,分解胞器中蛋白質以提供其他 細胞養分，當autophagy 持續進行則促進細胞死亡。FOXO3a 是一個transcriptional factor, 在生長因子刺激下FOXO3a 磷酸化,使FOXO3a 停留在細胞質,無法進入細胞核,導致無法 執行抑制細胞周期及啟動細胞死亡的功能。除了受磷酸化的調控,在氧化壓力下, FOXO3a 受乙醯轉化?(acetyltransferase) 如calcium response element-binding (CREB)-binding (CBP)及p300 將FOXO3a 上胺基酸lysine 乙醯化,引起細胞死亡。另外, 細胞骨架蛋白cortactin 也被p300 或CBP 乙醯化,無法與actin 結合,抑制了細胞遷移,因此 蛋白質乙醯化及去乙醯化在細胞的運動及生長扮演著重要功能。 另一方面,對cisplatin 治療產生抗藥性細胞中, FOXO3a 蛋白表現低,相反地,抑制 FOXO3a 乙醯化,增加了細胞生長及對cisplatin 抗藥性,這些結果顯示藉由藥物調控FOXO 蛋白表現量及乙醯化作用,是治療癌症及治療產生抗藥性癌症的一種策略。 植物中??類(anthraquinone)化合物如mitoxantrone, pixantrone 已被研發做為抗乳 癌、前列腺癌藥物。從蘭科植物分離出來的denbinobin 是phenanthrenequinone 類化合 物,與Fas ligand 併用對胰臟癌細胞的毒殺作用有加成性(synergistic)、並透過計畫性死 亡機制抑制老鼠腫瘤。吳等所研發之phenanthrenequinone 衍生物qui21 及相關衍生物, 在乳癌及攝護腺癌細胞,比denbinobin 具更低的IC50,因此我們將探討: qui21 及其衍生物 qui20 經由氧化或ER 壓力引起autophagy;另外是否FOXO3a、cortactin 乙醯化及磷酸化 對qui21 引起細胞死亡扮演重要角色;藉由何種乙醯轉化?參與FOXO3a、cortactin 乙 醯化;最後探討運用於對cisplatin 有抗藥性的攝護腺癌細胞治療的可能性。
One cellular response to fasting and oxidative stress is the activation autophagy. Autophagy-related genes (Atgs) and FOXO3a induce organelles to fuse with lysosome in which the organelles are degraded to provide nutrients. However, over-activated autophagy induces cell death. FOXO3a, a transcriptional factor, is phosphorylated by growth factor which is restricted in cytoplasma. Under oxidative stress, FOXO3a is dephosphorylated and then translocated to nucleus to promote cell cycle arrest and apoptosis. In addition, acetyltransferase, calcium response element-binding (CREB)-binding (CBP) or p300, acetylate FOXO3a which also results in cell apoptosis. In addition to FOXO3a, acetylation of cortactin by p300 inhibits interaction of cortactin with actin, which inhibits cell migration. Therefore, the regulation of protein acetylation plays an important role in cell migration and cell death. On the other hand, lower levels of FOXO3a are found in cisplatin resistance cells. Inhibition of Foxo3a acetylation increases cell proliferation and resistance to cisplatin. Thus, drug induced-FOXO3a expression and acetylation may be a strategy for treatment in cancer and chemotherapy resistance cancer. Anthraquinone is an aromatic organic compound and its derivatives, like mitoxantrone and pixantrone have been used to treat breast and prostate cancers. Denbinobin belongs to phenanthrenequinone and is isolated from Dendrobium nobile. Denbinobin has been reported to exhibit antitumor activity in mice bearing colon cancer cells. Combined treatment denbinobin with Fas ligand triggers a synergistic cytotoxic effect in human pancreatic adenocarcinoma cells. Here, Dr. Wu synthesizes a series of phenanthrenequinone derivatives, like qui20 and qui21 which have lower IC50 for breast and prostate cancer cells. We will determine whether oxidative or ER stress induces autophagy by qui21 and its derivates; whether acetylation of FOXO3a and cortactin are involved in qui21- and qui20- induced cell death; whether p300 or CBP is involved in acetylation of FOXO3a and cortactin; whether the combination of qui21 and cisplatin could be used for treatment of cisplatin resistance prostate cancers. |
