Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
Clin Cancer Res. 2012 Jul 15;18(14):3822-33. doi: 10.1158/1078-0432.CCR-11-3277. Epub 2012 May 23.
To characterize the importance of cellular Fas-associated death domain (FADD)-like interleukin 1β-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.
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.
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.
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.
描述细胞 Fas 相关死亡结构域（FADD）样白介素 1β 转换酶（FLICE）抑制蛋白（c-FLIP）的重要性，c-FLIP 是 caspase-8（FLICE）促进细胞凋亡的关键调节因子，在调节前列腺癌细胞对雄激素受体（AR）靶向治疗的反应中发挥作用。
通过前列腺切除术组织的免疫组织化学分析来描述 c-FLIP 的表达。通过分子和药理学干预研究 c-FLIP 对生存的功能重要性及其对比卡鲁胺反应的调节作用。
与正常前列腺上皮组织相比，高级别前列腺上皮内瘤变和前列腺癌组织中 c-FLIP 的表达增加（P < 0.001）。在去势抵抗性前列腺癌（CRPC；P < 0.001）中检测到最大的 c-FLIP 表达。在体外，沉默 c-FLIP 诱导自发凋亡，并通过流式细胞术、PARP 裂解和 caspase 活性测定增加 22Rv1 和 LNCaP 细胞对比卡鲁胺的敏感性。组蛋白去乙酰化酶抑制剂（HDACi）droxinostat 和 SAHA 也下调 c-FLIP 的表达，诱导 caspase-8 和 caspase-3/7 介导的凋亡，并增加比卡鲁胺处理细胞的凋亡。相反，在 CRPC 细胞系 VCaP 中检测到的 c-FLIP 表达升高，这解释了它们对体外比卡鲁胺和 SAHA 的不敏感性。然而，c-FLIP 的敲低在 VCaP 细胞中诱导自发凋亡，表明其与细胞存活和治疗抵抗有关。
c-FLIP 降低了 AR 靶向治疗的疗效，并维持了前列腺癌细胞的活力。使用 HDACi 联合雄激素剥夺疗法可能对早期疾病有效，将 c-FLIP 表达作为对敏感性的预测生物标志物。然而，直接靶向 c-FLIP 可能与增强现有和新型治疗药物在 CRPC 中的反应有关。
