Department of Medicine/Endocrinology, Weill Cornell Medicine, New York, NY 10065, USA.
Int J Oncol. 2017 Nov;51(5):1601-1610. doi: 10.3892/ijo.2017.4138. Epub 2017 Sep 27.
Chemotherapy is a vital therapeutic strategy for castration-resistant prostate cancer (CRPC). We have previously shown that NSC606985 (NSC), a camptothecin (CPT) analog, induced cell apoptosis via interacting with topoisomerase I (Topo I) in prostate cancer cells. In the present study, the effect and mechanism of CPT analogs in LAPC4 cells were investigated. LAPC-4 cells were treated with NSC, CPT, and topotecan. Cell proliferation, apoptosis, and protein kinase Cδ (PKCδ) subcellular activation were measured at different doses and time-points, with or without PKCδ inhibition or knockdown of PKCδ expression. NSC at doses ranging from 10 to 100 nM induced a dose-dependent increase in viable cell number and DNA biosynthesis with mild cell apoptosis, whereas, at doses ranging from 500 nM to 5 mM, NSC produced a dose-dependent decrease in cell proliferation and DNA biosynthesis with a significant induction of cell apoptosis. Both NSC-induced cell proliferation and apoptosis were blocked by knockdown of PKCδ with a specific RNAi, or by the co-administration of rottlerin, a PKCδ inhibitor. Moreover, NSC produced a dose-dependent subcellular activation of PKCδ. The dose-dependent dual action of NSC is mediated at least in part through the differential subcellular activation of PKCδ in LAPC4 cells. The demonstration of a differential cell response to camptothecin analogs would facilitate the identification of biomarker(s) to CPT sensitivity and promote the personalization of CPT chemotherapy in CRPC.
化疗是去势抵抗性前列腺癌（CRPC）的重要治疗策略。我们之前已经表明，喜树碱（CPT）类似物 NSC606985（NSC）通过与前列腺癌细胞中的拓扑异构酶 I（Topo I）相互作用诱导细胞凋亡。在本研究中，研究了 CPT 类似物在 LAPC4 细胞中的作用和机制。用 NSC、CPT 和拓扑替康处理 LAPC-4 细胞。在不同剂量和时间点，测量细胞增殖、凋亡和蛋白激酶 Cδ（PKCδ）亚细胞激活情况，有或没有 PKCδ 抑制或 PKCδ 表达敲低。10 至 100 nM 的 NSC 剂量依赖性地增加活细胞数量和 DNA 生物合成，伴有轻度细胞凋亡，而 500 nM 至 5 mM 的 NSC 剂量依赖性地降低细胞增殖和 DNA 生物合成，显著诱导细胞凋亡。用特定的 RNAi 敲低 PKCδ 或联合使用 PKCδ 抑制剂罗特林均可阻断 NSC 诱导的细胞增殖和凋亡。此外，NSC 产生剂量依赖性的 PKCδ 亚细胞激活。NSC 的这种剂量依赖性双重作用至少部分是通过 LAPC4 细胞中 PKCδ 的差异亚细胞激活介导的。对喜树碱类似物的细胞反应差异的证明将有助于确定 CPT 敏感性的生物标志物，并促进 CRPC 中 CPT 化疗的个体化。
