Li Jun, Vesey David A, Johnson David W, Gobe Glenda
Centre for Kidney Disease Research UQ/PAH and Discipline of Molecular and Cellular Pathology, School of Medicine, University of Queensland, Herston, Brisbane, Australia.
Cancer Biol Ther. 2007 Dec;6(12):1944-50. doi: 10.4161/cbt.6.12.4975. Epub 2007 Sep 1.
Anaemia which develops as a consequence of malignancies is often treated using recombinant human erythropoietin (rhEpo). Epo is now known as an anti-apoptotic factor for a wide range of cell types that express Epo receptors (EpoRs) and its co-use with cancer therapies can act detrimentally to diminish therapy-induced apoptosis. This had not been analyzed for renal cell carcinomas (RCCs). We examined the influence of rhEPO on the ability of cisplatin to induce apoptosis in RCCs. Two RCC cell lines (SN12K1 and ACHN) were compared with a non-RCC renal epithelial cell line (HK2). Cells were treated with 50 microM cisplatin with and without 200 IU/mL rhEpo and were compared for apoptosis, mitosis and protein expression of EpoR, nuclear factor-kappaB (NFkappaB), protein kinase C (PKC), Bcl-2, Bax and cyclin-D1. Experiments were repeated with PKC promotion (PMA, 20 nM) or inhibition (H7, 10 microM). rhEpo reduced cisplatin-induced apoptosis in RCCs (p < 0.01), compared with HK-2s. EpoR expression was increased only in SN12K1 with rhEpo, with and without cisplatin. NFkappaB, Bax and Bcl-2 expression was unchanged. PKC protein expression was significantly reduced in cisplatin-treated RCCs with rhEpo, correlating with reduced apoptosis. When the PKC pathway was inhibited in these cells, levels o apoptosis returned to normal for cisplatin treatment, indicating activation of the PKC pathway by rhEpo. PMA promotion increased mitosis only in the RCCs, with and without rhEpo (p < 0.05). In summary, rhEPO reduced cisplatin-induced apoptosis of RCCs and promoted their mitosis via PKC-dependent pathways. This information indicates caution for use of rhEpo in RCC patients for anemias.
因恶性肿瘤而引发的贫血通常采用重组人促红细胞生成素（rhEpo）进行治疗。如今已知Epo是多种表达促红细胞生成素受体（EpoRs）的细胞类型的抗凋亡因子，并且它与癌症疗法共同使用可能会产生不利影响，减少治疗诱导的细胞凋亡。肾细胞癌（RCC）尚未对此进行分析。我们研究了rhEPO对顺铂诱导RCC细胞凋亡能力的影响。将两种RCC细胞系（SN12K1和ACHN）与一种非RCC肾上皮细胞系（HK2）进行比较。细胞分别用50微摩尔顺铂处理，同时添加和不添加200国际单位/毫升rhEpo，比较细胞凋亡、有丝分裂以及EpoR、核因子-κB（NFκB）、蛋白激酶C（PKC）、Bcl-2、Bax和细胞周期蛋白D1的蛋白表达。使用蛋白激酶C促进剂（佛波酯，20纳摩尔）或抑制剂（H7，10微摩尔）重复实验。与HK-2细胞相比，rhEpo减少了顺铂诱导的RCC细胞凋亡（p < 0.01）。无论有无顺铂，rhEpo仅使SN12K1细胞中的EpoR表达增加。NFκB、Bax和Bcl-2的表达没有变化。在经顺铂处理的RCC细胞中，rhEpo使PKC蛋白表达显著降低，这与细胞凋亡减少相关。当这些细胞中的PKC途径被抑制时，顺铂处理的细胞凋亡水平恢复正常，表明rhEpo激活了PKC途径。佛波酯促进仅在有或没有rhEpo的RCC细胞中增加有丝分裂（p < 0.05）。总之，rhEPO减少了顺铂诱导的RCC细胞凋亡，并通过PKC依赖途径促进其有丝分裂。这一信息表明在RCC患者贫血治疗中使用rhEpo时需谨慎。
