Wilson Catherine, Wilson Timothy, Johnston Patrick G, Longley Daniel B, Waugh David J J
Centre for Cancer Research and Cell Biology, Queens University Belfast, 97 Lisburn Road, Belfast, Northern Ireland BT9 7BL, United Kingdom.
Mol Cancer Ther. 2008 Sep;7(9):2649-61. doi: 10.1158/1535-7163.MCT-08-0148.
Chemotherapy-induced interleukin-8 (IL-8) signaling reduces the sensitivity of prostate cancer cells to undergo apoptosis. In this study, we investigated how endogenous and drug-induced IL-8 signaling altered the extrinsic apoptosis pathway by determining the sensitivity of LNCaP and PC3 cells to administration of the death receptor agonist tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL induced concentration-dependent decreases in LNCaP and PC3 cell viability, coincident with increased levels of apoptosis and the potentiation of IL-8 secretion. Administration of recombinant human IL-8 was shown to increase the mRNA transcript levels and expression of c-FLIP(L) and c-FLIP(S), two isoforms of the endogenous caspase-8 inhibitor. Pretreatment with the CXCR2 antagonist AZ10397767 significantly attenuated IL-8-induced c-FLIP mRNA up-regulation whereas inhibition of androgen receptor- and/or nuclear factor-kappaB-mediated transcription attenuated IL-8-induced c-FLIP expression in LNCaP and PC3 cells, respectively. Inhibition of c-FLIP expression was shown to induce spontaneous apoptosis in both cell lines and to sensitize these prostate cancer cells to treatment with TRAIL, oxaliplatin, and docetaxel. Coadministration of AZ10397767 also increased the sensitivity of PC3 cells to the apoptosis-inducing effects of recombinant TRAIL, most likely due to the ability of this antagonist to block TRAIL- and IL-8-induced up-regulation of c-FLIP in these cells. We conclude that endogenous and TRAIL-induced IL-8 signaling can modulate the extrinsic apoptosis pathway in prostate cancer cells through direct transcriptional regulation of c-FLIP. Therefore, targeted inhibition of IL-8 signaling or c-FLIP expression in prostate cancer may be an attractive therapeutic strategy to sensitize this stage of disease to chemotherapy.
化疗诱导的白细胞介素-8（IL-8）信号传导降低了前列腺癌细胞发生凋亡的敏感性。在本研究中，我们通过测定LNCaP和PC3细胞对死亡受体激动剂肿瘤坏死因子相关凋亡诱导配体（TRAIL）给药的敏感性，来研究内源性和药物诱导的IL-8信号传导如何改变外源性凋亡途径。TRAIL诱导LNCaP和PC3细胞活力呈浓度依赖性下降，同时凋亡水平增加且IL-8分泌增强。给予重组人IL-8可增加内源性半胱天冬酶-8抑制剂的两种同工型c-FLIP(L)和c-FLIP(S)的mRNA转录水平和表达。用CXCR2拮抗剂AZ10397767预处理可显著减弱IL-8诱导的c-FLIP mRNA上调，而抑制雄激素受体和/或核因子-κB介导的转录分别减弱了LNCaP和PC3细胞中IL-8诱导的c-FLIP表达。抑制c-FLIP表达可诱导两种细胞系自发凋亡，并使这些前列腺癌细胞对TRAIL、奥沙利铂和多西他赛治疗敏感。联合给予AZ10397767也增加了PC3细胞对重组TRAIL凋亡诱导作用的敏感性，这很可能是由于该拮抗剂能够阻断这些细胞中TRAIL和IL-8诱导的c-FLIP上调。我们得出结论，内源性和TRAIL诱导的IL-8信号传导可通过对c-FLIP的直接转录调控来调节前列腺癌细胞的外源性凋亡途径。因此，在前列腺癌中靶向抑制IL-8信号传导或c-FLIP表达可能是使该疾病阶段对化疗敏感的一种有吸引力的治疗策略。
