Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Mol Cancer Ther. 2013 Aug;12(8):1568-78. doi: 10.1158/1535-7163.MCT-12-1010. Epub 2013 May 8.
Advanced renal cell carcinoma (RCC) is an invariably fatal cancer. Currently, small-molecule inhibitors that target cell growth, angiogenesis, or nutrient-sensing pathways represent the primary pharmacologic interventions for this disease, but these inhibitors only delay tumor progression and are not curative. The cytokine IFN-γ showed the potential to provide lasting remission in several phase I/II trials for advanced RCCs, but subsequent trials, including a multicenter phase III study using IFN-γ as a monotherapy for RCCs, were less promising. Notably, these trials were designed to exploit the indirect immunomodulatory effects of IFN-γ, whereas its direct antitumor properties--including its ability to trigger programmed cell death in tumors-remain mostly untapped. Here, we show that the proteasome inhibitor bortezomib (PS-341, Velcade) sensitizes otherwise resistant RCC cells to direct necrotic death by IFN-γ. Mechanistically, we show that bortezomib functions, at least in part, by inhibiting prosurvival NF-κB signaling. In the absence of this signal, IFN-γ triggers programmed necrosis (or "necroptosis") dependent on the kinase RIP1. When taken together with the observation that NF-κB signaling is elevated in RCCs, these results provide rationale for the combined use of IFN-γ and bortezomib in the treatment of metastatic RCCs.
晚期肾细胞癌（RCC）是一种致命的癌症。目前，针对细胞生长、血管生成或营养感应途径的小分子抑制剂是治疗这种疾病的主要药物干预措施，但这些抑制剂只能延缓肿瘤进展，而不能治愈。细胞因子 IFN-γ 在几项针对晚期 RCC 的 I/II 期试验中显示出提供持久缓解的潜力，但随后的试验，包括一项使用 IFN-γ 作为 RCC 单一疗法的多中心 III 期研究，结果并不那么有希望。值得注意的是，这些试验旨在利用 IFN-γ 的间接免疫调节作用，而其直接抗肿瘤特性--包括其在肿瘤中触发程序性细胞死亡的能力--仍未得到充分利用。在这里，我们表明蛋白酶体抑制剂硼替佐米（PS-341，Velcade）使原本耐药的 RCC 细胞对 IFN-γ 产生直接坏死性死亡敏感。从机制上讲，我们表明硼替佐米至少部分通过抑制生存 NF-κB 信号起作用。在没有这种信号的情况下，IFN-γ 触发依赖于激酶 RIP1 的程序性坏死（或“坏死性凋亡”）。当与 NF-κB 信号在 RCC 中升高的观察结果结合在一起时，这些结果为 IFN-γ 和硼替佐米联合用于治疗转移性 RCC 提供了合理的依据。
