Blockade of NFκB activity by Sunitinib increases cell death in Bortezomib-treated endometrial carcinoma cells
Blockade of NFκB activity by Sunitinib increases cell death in Bortezomib-treated endometrial carcinoma cells
复制标题
DOI：
10.1016/j.molonc.2012.06.006
复制
发表时间：
2012-10-01
影响因子：
6.6
通讯作者：
Matias-Guiu, Xavier
中科院分区：
文献类型：
--
作者：
Sorolla, Anabel;Yeramian, Andree;Matias-Guiu, Xavier
子宫内膜癌是女性生殖道最常见的恶性肿瘤之一，通常通过手术和放射治疗来治疗。当子宫内膜癌伴有广泛转移或放射治疗后肿瘤复发时，使用化疗。在本研究中，我们证明酪氨酸激酶受体抑制剂舒尼替尼可降低子宫内膜癌细胞系中的细胞活力、增殖、克隆性并诱导细胞凋亡，这不是由于其通过 VEGFR 等最著名的靶点发挥作用，也不是通过本研究中证明的 EGFR 发挥作用。有趣的是，舒尼替尼可在基础水平或 EGF 或 TNF-α 的激活下降低 NF kappa B 转录活性。我们观察到舒尼替尼能够抑制硼替佐米诱导的 NF kappa B 转录活性，这与 IKK α 和 β、p65 和 I kappa B α 磷酸化水平的降低相关。我们通过剂量效应法评估了舒尼替尼和硼替佐米之间相互作用的性质，并确定了协同效应（组合指数<1）。类似地，在硼替佐米处理的细胞中，通过慢病毒介导的短发夹RNA递送沉默p65表达，导致对硼替佐米凋亡细胞死亡的敏感性大大增加。总而言之，我们的结果表明，舒尼替尼和硼替佐米的组合可以被认为是手术和放疗失败后子宫内膜癌的一种有前途的治疗方法。 (C) 2012 年欧洲生化学会联合会。由 Elsevier B.V. 出版。保留所有权利。
Endometrial carcinoma is one of the most common malignancies in the female genital tract, usually treated by surgery and radiotherapy. Chemotherapy is used when endometrial carcinoma is associated with widespread metastasis or when the tumor recurs after radiation therapy. In the present study, we demonstrate that the tyrosine kinase receptor inhibitor Sunitinib reduces cell viability, proliferation, clonogenicity and induces apoptotic cell death in endometrial carcinoma cell lines, which is not due to its action through the most known targets like VEGFR, nor through EGFR as demonstrated in this work. Interestingly, Sunitinib reduces NF kappa B transcriptional activity either at basal level or activation by EGF or TNF-alpha. We observed that Sunitinib was able to inhibit the Bortezomib-induced NF kappa B transcriptional activity which correlates with a decrease of the phosphorylated levels of IKK alpha and beta, p65 and I kappa B alpha. We evaluated the nature of the interaction between Sunitinib and Bortezomib by the dose effect method and identified a synergistic effect (combination index < 1). Analogously, silencing of p65 expression by lentiviral-mediated short-hairpin RNA delivery in Bortezomib treated cells leads to a strongly increased sensitivity to Bortezomib apoptotic cell death. Altogether our results suggest that the combination of Sunitinib and Bortezomib could be considered a promising treatment for endometrial carcinoma after failure of surgery and radiation. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.