Lytic peptide-mediated sensitization of TRAIL-resistant prostate cancer cells to death receptor agonists
Lytic peptide-mediated sensitization of TRAIL-resistant prostate cancer cells to death receptor agonists
复制标题
DOI：
10.1016/j.canlet.2010.01.012
复制
发表时间：
2010-07-28
期刊：
影响因子：
9.7
通讯作者：
Rege, Kaushal
中科院分区：
文献类型：
--
作者：
Barua, Sutapa;Linton, Rebecca S.;Rege, Kaushal
肿瘤坏死因子-α相关凋亡诱导配体（TRAIL）和死亡受体（DR）4和5的激动性抗体近年来引起了人们的极大关注，因为它们能够选择性地诱导恶性细胞的凋亡，同时在正常细胞中表现出很小的细胞毒性。尽管这些候选物在癌症治疗中是有希望的，但许多肿瘤细胞对TRAIL介导的凋亡具有抗性。我们描述了阳离子两亲性裂解肽KLA（单字母序列HHHHHKLAK-LAKKLAKLAKC）用于TRAIL抗性LNCaP和PC 3-PSMA人前列腺癌细胞对DR激动性抗体的化学增敏的用途。用DR激动性抗体的“单一药剂”处理没有导致这些细胞的活力丧失，证实了这些细胞的抗性。然而，与单独作用的单独治疗相比，KLA随后DR激动剂的组合治疗导致更大的细胞死亡，表明组合治疗的两种组分之间的协同作用。裂解肽和DR激动剂的组合导致细胞中活化的半胱天冬酶-3切割和细胞色素-C蛋白水平的显著增加，表明半胱天冬酶介导的凋亡途径的作用。此外，KLA处理还导致DR 5和脂筏在LNCaP细胞中的定位增加。我们的研究结果表明，第一次，裂解肽可用于敏感的TRAIL-耐药的前列腺癌细胞DR-介导的细胞凋亡，导致新的组合治疗晚期癌细胞的消融。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Tumor Necrosis Factor-a Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptors (DR) 4 and 5 have attracted significant attention in recent years due to their ability to selectively induce apoptosis in malignant cells while demonstrating little cytotoxicity in normal cells. Although these candidates are promising in cancer therapy, a number of tumor cells are resistant to TRAIL-mediated apoptosis. We describe the use of a cationic amphipathic lytic peptide, KLA (single letter sequence HHHHHKLAK-LAKKLAKLAKC), for the chemosensitization of TRAIL-resistant LNCaP and PC3-PSMA human prostate cancer cells to DR agonistic antibodies. 'Single-agent' treatment with DR agonistic antibodies did not result in loss of viability of these cells confirming the resistance of these cells. However, the combination treatment of KLA followed by DR agonists resulted in greater cell death compared to the individual treatments acting alone, indicating synergistic action between the two components of the combination treatment. The combination of lytic peptide and DR agonists resulted in a significant increase in activated caspase-3 cleavage and cytochrome-C protein levels in cells, indicating a role for the caspase-mediated apoptotic pathway. In addition, KLA treatment also resulted in increased localization of DR5 and lipid rafts in LNCaP cells. Our results demonstrate, for the first time, that lytic peptides can be employed for sensitizing TRAIL-resistant prostate cancer cells to DR-mediated apoptosis resulting in novel combination treatments for the ablation of advanced cancer cells. (C) 2010 Elsevier Ireland Ltd. All rights reserved.