探討Securin在ACP-93誘發細胞凋亡和抗腫瘤形成作用的角色

The role of securin in apoptosis and anti-tumorigenesis induced by ACP-93

10.6842/NCTU.2011.00478

簡佩萱

腦下垂體腫瘤轉型基因-1 ； 細胞凋亡 ； 腫瘤新生 ； securin ； PTTG-1 ； apoptosis ； tumorigenesis

交通大學分子醫學與生物工程研究所學位論文

2011年

碩士

趙瑞益

繁體中文

Securin又名腦下垂體腫瘤轉型基因，能促進癌細胞增生及腫瘤形成。ACP-93是一種由UK-1衍生的新合成化合物。在本研究中我們探討ACP-93處理人類大腸癌細胞後，誘發細胞凋亡與抑制腫瘤形成的抗癌活性，以及securin可能扮演的調控角色。ACP-93都會誘發securin功能正常與缺乏的HCT116人類大腸癌細胞之凋亡。以4-32 μM ACP-93處理24小時，誘發caspase 3和caspase 8的活化，以及造成PARP蛋白的分解。ACP-93同時誘發ATF-3蛋白與磷酸化H2AX蛋白的表現。再者，ACP-93誘發磷酸化AKT蛋白的增加。以wortmannin共同處理抑制AKT路徑後，會增加ACP-93所誘發的細胞毒性。更重要是ACP-93具有顯著抑制嚴重免疫缺失的老鼠與裸鼠中之異體移植人類大腸腫瘤的形成作用。此外，缺乏securin的HCT116大腸癌細胞在異體移植裸鼠中的腫瘤生長能力，比正常表現securin的HCT116癌細胞較差。由這些發現，ACP-93具有誘發細胞凋亡和抗腫瘤的形成能力，而securin能促進腫瘤形成的作用。

Securin, also known as pituitary-tumor transforming gene, promotes cancer cell proliferation and tumorigenesis. ACP-93 is novel synthetic compound that is derivative from UK-1. In this study, we investigated the anticancer abilities in apoptosis induction and tumor inhibition and the possible role of securin by ACP-93 in the human colon cancer. ACP-93 induced apoptosis in both the HCT116 securin-wild type and securin-null colon cancer cells. Treatment with ACP-93 (4-32 μM for 24 h) induced the activation of caspase 3 and caspase 8 and the protein cleavage of PARP in colon cancer cells. Meanwhile, ACP-93 induced the protein expression of ATF-3 and the phosphorylation of H2AX. Furthermore, ACP-93 increased the phosphorylation of AKT. The blockade of AKT pathway by co-treatment with wortmannin increased the ACP-93-induced cytotoxicity. More importantly, ACP-93 significantly inhibited the tumorigenesis of xenograft human colon tumors in severe combined immunodeficiency (SCID) and nude mice. Besides, the tumor growth ability in the HCT116 securin-null colon cancer cells was less than the securin-wild type HCT116 in xenograft nude mice. In summary, the findings indicate that ACP-93 induces apoptosis and anti-tumorigenesis in colon cancer, and securin can promote tumorigenesis.