| Abstract: | 鳥胺酸去羧化（ornithine decarboxylase；ODC，EC 4. 1. 1. 17）為體內多胺酸（包括腐胺、亞精胺及精胺）合成起始與速率決定步驟酵素，主要功能為催化L-鳥胺酸形成腐胺及二氧化碳，腐胺及ODC在許多細胞生理功能包括細胞生長、分化及死亡上佔有重要的角色。cis-Diammin-dichloro-platinumII（cisplatin; CDDP）、etoposide（VP-16）及paclitaxel（taxol; TAX）是現今普遍被使用於治療惡性腫瘤的化學治療藥物。CDDP在進入細胞後與DNA形成化合物（CDDP-DNA adducts），造成DNA結構的變化，使得DNA原先的雙股螺旋結構變形，導致DNA無法纏繞或捲縮，最後使得DNA合成受到抑制，進而產生細胞毒性造成細胞死亡。VP-16的藥理作用機制為對topoisomerase II的抑制，藉此阻礙DNA之重接合作用(relegation)而導致DNA的損傷，最後造成癌細胞死亡。TAX改變tubulin subunit的結構，強力的抑制tubulin heterodimer之解離，導致細胞分裂被抑制，造成癌症細胞死亡。在實驗室先前的研究當中，高度表現的ODC可藉由減少細胞內活性氧（reactive oxygen species ；ROS）的產生來抵抗TNF-alpha及methotresxate所引發之細胞凋亡。在本研究中，這些抗癌藥物皆能產生ROS的聚積，進而破壞粒腺體膜電位（mitochondrial membrane potential），最後造成細胞凋亡。此外ODC亦可藉由減少細胞內ROS的聚積、提高Bcl-2表現、維持粒腺體膜電位、阻止cytochrome c釋放至細胞質及抑制caspases的活化來抵抗細胞凋亡。另外一方面，ODC亦將細胞休止在G1期。細胞在處理抗癌藥物後，ODC仍可藉由提高cycylin-dependent kinase（CDK）2及CDK1的活性來抵抗細胞凋亡。綜歸以上的實驗結果顯示出，ODC抵抗細胞凋亡的機制除了抑制粒腺體之細胞凋亡路徑，亦經由細胞週期的調控來抑制細胞凋亡。
Ornithine decarboxylase(ODC；EC 4.1.1.17)is the first and rate-limiting enzyme of the polyamine(putrescine, spermidine and spermine) biosynthetic pathway, which decarboxylates L-ornithine to form putrescine. ODC and polyamines play a key role in normal biological functions, including embryonic development, cell cycle, proliferation, differentiation and cell death. cis-Diammin-dichloro-platinumII (cisplatin; CDDP), etoposide (VP-16) and paclitaxel (taxol; TAX) represent a unique and important class of antitumor agents. CDDP causes apoptosis by generating DNA and protein adducts that include DNA-protein cross-links, DNA monoadducts, inter-and intra-strand DNA cross-links, protein-protein cross-links, and protein adducts. VP-16 stabilizes topoisomerase II-DNA cleavable complex, thereby inducing a series of events in various cell types that can eventually lead to cell cycle arrest at the G1 phase and apoptosis. TAX stabilizes tubulin dimmers, thus interfering with microtubular disassembly, resulting in the arrest of cells in G2/M phase of the cell cycle, followed by DNA fragmentation and morphological features of apoptosis. In our precedented studies, ODC overexpression cells are resistant to TNF-alpha and methotrexate-induced apoptosis by reducing intracellular reactive oxygen species (ROS) production. Here, we also found ODC prevents antitumor agents-induced apoptosis by decreasing intracellular ROS to avoid Bcl-2 decline, maintain mitochondrial membrane potential, prevent cytochrome c release from mitochondria and inhibited the activation of caspase 9 and 3. Besides, ODC significantly arrests cells in G1 phase. In the detections of kinase activity, cycylin-dependent kinase (CDK) 2 and CDK1 enzyme activities are increases by overexpression of ODC. According to these data, we suggest that ODC prevents apoptosis through cell cycle arrest and mitochondria-mediated pathway. |
