Nakai Yasushi, Miyake Makito, Morizawa Yosuke, Hori Shunta, Tatsumi Yoshihiro, Anai Satoshi, Onishi Sayuri, Tanaka Nobumichi, Fujimoto Kiyohide
Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
Oncol Rep. 2017 Jan;37(1):227-234. doi: 10.3892/or.2016.5232. Epub 2016 Nov 8.
We examined extracellular signal‑regulated kinase (ERK), 4E‑binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70) as potential biomarkers for pretreatment prediction of the prognosis of patients with metastatic renal cell carcinoma (RCC) treated with sorafenib, sunitinib or everolimus. 786‑O and 769‑P cells were treated with sorafenib, sunitinib and everolimus. The expression of phosphorylated/total ERK, phosphorylated/total 4EBP1 and phosphorylated/total p70 was evaluated using western blotting. ERK, 4EBP1 and p70 were knocked down by siRNA in 786‑O and 769‑P cells. Then, the viability after treatment with each drug was assessed. Expression of phosphorylated (phospho)‑ERK, -4EBP1 and -p70 was immunohistochemically evaluated in radical nephrectomy specimens and correlated with progression‑free survival during treatment with each molecular targeting agent. Sorafenib inhibited the expression of phospho-ERK and -4EBP1 in 769‑P cells; sunitinib, phospho-ERK and -4EBP1 in 786‑O and 769‑P cells; and everolimus, phospho-p70 in 786‑O and 769‑P cells. Knockdown of ERK reduced sensitivity to sorafenib in both cell lines, knockdown of ERK and 4EBP1 reduced sensitivity to sunitinib in 769‑P cells, and knockdown of 4EBP1 and p70 reduced sensitivity to everolimus in 786‑O cells. High expression of phospho-ERK, -4EBP1 and -p70 correlated with better progression‑free survival in patients treated with sorafenib, sunitinib and everolimus, respectively. Our results indicate that phospho-ERK, -4EBP1 and/or -ERK, and phospho-p70 can be used as biomarkers for the therapeutic efficacy of sorafenib, sunitinib and everolimus, respectively.
我们检测了细胞外信号调节激酶（ERK）、4E结合蛋白1（4EBP1）和p70核糖体S6激酶（p70），作为索拉非尼、舒尼替尼或依维莫司治疗的转移性肾细胞癌（RCC）患者预后的预处理预测潜在生物标志物。用索拉非尼、舒尼替尼和依维莫司处理786-O和769-P细胞。使用蛋白质印迹法评估磷酸化/总ERK、磷酸化/总4EBP1和磷酸化/总p70的表达。在786-O和769-P细胞中，通过小干扰RNA（siRNA）敲低ERK、4EBP1和p70。然后，评估每种药物处理后的细胞活力。在根治性肾切除标本中，通过免疫组织化学评估磷酸化（磷酸化）-ERK、-4EBP1和-p70的表达，并与每种分子靶向药物治疗期间的无进展生存期相关。索拉非尼抑制769-P细胞中磷酸化-ERK和-4EBP1的表达；舒尼替尼抑制786-O和769-P细胞中磷酸化-ERK和-4EBP1的表达；依维莫司抑制786-O和769-P细胞中磷酸化-p70的表达。在两种细胞系中，敲低ERK降低了对索拉非尼的敏感性，在769-P细胞中，敲低ERK和4EBP1降低了对舒尼替尼的敏感性，在786-O细胞中，敲低4EBP1和p70降低了对依维莫司的敏感性。磷酸化-ERK、-4EBP1和-p70的高表达分别与接受索拉非尼、舒尼替尼和依维莫司治疗的患者更好的无进展生存期相关。我们的结果表明，磷酸化-ERK、-4EBP1和/或-ERK以及磷酸化-p70可分别用作索拉非尼、舒尼替尼和依维莫司治疗效果的生物标志物。
