Elevation of c-FLIP in Castrate-Resistant Prostate Cancer Antagonizes Therapeutic Response to Androgen Receptor-Targeted Therapy
Elevation of c-FLIP in Castrate-Resistant Prostate Cancer Antagonizes Therapeutic Response to Androgen Receptor-Targeted Therapy
复制标题
DOI：
10.1158/1078-0432.ccr-11-3277
复制
发表时间：
2012-07-15
影响因子：
11.5
通讯作者：
Waugh, David J. J.
中科院分区：
文献类型：
--
作者：
McCourt, Clare;Maxwell, Pamela;Waugh, David J. J.
目的：探讨细胞Fas相关死亡结构域(FADD)样白介素1β转换酶(FLICE)抑制蛋白在调节前列腺癌细胞对雄激素受体(AR)靶向治疗反应中的作用。结果：与正常前列腺组织相比，高级别前列腺上皮内瘤变和前列腺癌组织中c-FLIP的表达明显增加(P<；0.001)。在去势抵抗型前列腺癌(CRPC；P<；0.001)中检测到最大的c-FLIP表达。在体外，通过流式细胞仪、PARP裂解和半胱氨酸天冬氨酸氨基转移酶(Caspase)活性检测，沉默c-flip可诱导自发的细胞凋亡，并增加22Rv1和LNCaP细胞对比卡鲁胺的敏感性。组蛋白去乙酰酶抑制剂(HDACi)、去氧磷酸盐和SAHA也下调c-flip的表达，诱导caspase-8和caspase-3/7介导的细胞凋亡，并增加比卡鲁胺处理后的细胞凋亡率。相反，在CRPC细胞系VCaP中检测到的c-Flip表达的升高，在体外支持了它们对比卡鲁胺和SAHA的不敏感。但c-FLIP基因敲除可诱导VCaP细胞自发性凋亡，提示其与细胞存活和治疗耐药有关。结论：c-FLIP降低了AR靶向治疗的疗效，维持了前列腺癌细胞的活力。HDACi与雄激素剥夺疗法的结合可能对早期疾病有效，使用c-Flip表达作为敏感性的预测生物标记物。然而，c-FLIP的直接靶向可能与增强现有和新疗法对CRPC的反应有关。临床癌症研究；18(14)；3822-33。(C)2012年AACR。
Purpose: To characterize the importance of cellular Fas-associated death domain (FADD)-like interleukin 1 beta-converting enzyme (FLICE) inhibitory protein (c-FLIP), a key regulator of caspase-8 (FLICE)-promoted apoptosis, in modulating the response of prostate cancer cells to androgen receptor (AR)-targeted therapy.Experimental Design: c-FLIP expression was characterized by immunohistochemical analysis of prostatectomy tissue. The functional importance of c-FLIP to survival and modulating response to bicalutamide was studied by molecular and pharmacologic interventions.Results: c-FLIP expression was increased in high-grade prostatic intraepithelial neoplasia and prostate cancer tissue relative to normal prostate epithelium (P < 0.001). Maximal c-FLIP expression was detected in castrate-resistant prostate cancer (CRPC; P < 0.001). In vitro, silencing of c-FLIP induced spontaneous apoptosis and increased 22Rv1 and LNCaP cell sensitivity to bicalutamide, determined by flow cytometry, PARP cleavage, and caspase activity assays. The histone deacetylase inhibitors (HDACi), droxinostat and SAHA, also downregulated c-FLIP expression, induced caspase-8- and caspase-3/7-mediated apoptosis, and increased apoptosis in bicalutamide-treated cells. Conversely, the elevated expression of c-FLIP detected in the CRPC cell line VCaP underpinned their insensitivity to bicalutamide and SAHA in vitro. However, knockdown of c-FLIP induced spontaneous apoptosis in VCaP cells, indicating its relevance to cell survival and therapeutic resistance.Conclusion: c-FLIP reduces the efficacy of AR-targeted therapy and maintains the viability of prostate cancer cells. A combination of HDACi with androgen deprivation therapy may be effective in early-stage disease, using c-FLIP expression as a predictive biomarker of sensitivity. Direct targeting of c-FLIP, however, may be relevant to enhance the response of existing and novel therapeutics in CRPC. Clin Cancer Res; 18(14); 3822-33. (C)2012 AACR.