Reseazrhof cell surface aminopeptidase function and translational in chemomcistance of gynecologic cancer

在这项研究中，我们研究了P-LAP/IRAP是否改变了凋亡调节蛋白的表达，作为耐药的一个机制。将P-LAP/IRAP基因导入子宫内膜腺癌细胞系A-MEC，细胞对紫杉醇、卡铂和顺铂的I050分别增加1.8倍、2.0倍和1.7倍。卡铂处理的A-MEC-PC细胞显示出更强的PARP裂解，与caspase裂解的增加相当，而A-MEC-LAP细胞没有表达裂解的PARR。这些结果表明，P-LAP/IRAP通过抑制线粒体介导的细胞凋亡而降低了对抗癌药物的敏感性，可能是克服抗癌耐药的分子靶点。此外，我们研究了P-LAP/IRAP增强子宫内膜癌的恶性潜能是否由于P-LAP/IRAP介导的胰岛素信号的激活而增加了葡萄糖摄取。A-MEC-LAP细胞表达高水平的GLUT4蛋白。A-MEC-LAP细胞对胰岛素反应的311-2-脱氧葡萄糖摄取量明显高于A-MEC-PC细胞。P-LAP/IRAP参与了胰岛素介导的子宫内膜癌恶性潜能的增加。P-LAP/IRAP被认为是子宫内膜癌分子靶向治疗的潜在新靶点。接下来，我们探讨了APN/CD13是否改变了细胞凋亡调节蛋白的表达作为耐药机制。APN/CD13抑制剂Bestatin可抑制卵巢癌细胞对紫杉醇的耐药性。APN/CD13的Bestatin和siRNA通过抑制线粒体介导的细胞凋亡而增加对抗癌药物(紫杉醇)的敏感性。APN/CD13有望成为卵巢癌分子靶向治疗的新靶点。

In this study, we investigated whether P-LAP/IRAP alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. We transfected P-LAP/IRAP cDNA into endometrial adenocarcinoma cell line (A-MEC), andA-MEC-LAP cells displayed a 1.8-fold, 2.0-fold, and 1.7-fold increase in I050 against paclitaxel, carboplatin, and cisplatin respectively. While treatment of A-MEC-pc cells with carboplatin showed a much stronger PARP cleavage, comparable to the increase observed in cleaved caspases, A-MEC-LAP cells did not show any expression of cleaved PARR These results suggest that P-LAP/IRAP reduces sensitivity to anticancer drugs via inhibition of mitochondria-mediated apoptosis, and may be a molecular target for conquering anticancer drug resistance. Furthermore, we examined whether the malignant potential of endometrial cancer enhanced by P-LAP/IRAP is due to increased glucose uptake via the P-LAP/IRAP-mediated activation of insulin signaling. A-MEC-LAP cells expressed a remarkably high level of GLUT4 proteins. 311-2-deoxyglucose uptake which responds to insulin in A-MEC-LAP cells was significantly higher than that of A-MEC-pc cells. P-LAP/IRAP was involved in the increasing malignant potential of endometrial cancer mediated by insulin. P-LAP/IRAP was suggested to be a potential new target of molecular-targeted therapy for endometrial cancer.Next, we examined whether APN/CD13 alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. APN/CD13 inhibitor, bestatin inhibited the paclitaxel resistance in ovarian cancer cells. Bestatin and siRNAof APN/CD13 increased sensitivity to anticancer drugs (paclitaxel) via inhibition of mitochondria-mediated apoptosis. APN/CD13 was suggested to be a potential new target of molecular-targeted therapy for ovarian cancer.