School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.
Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation, UCSF, San Francisco, CA 94158, USA.
Sci Transl Med. 2018 May 2;10(439). doi: 10.1126/scitranslmed.aar2036.
Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2-α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure.
致癌病变上调能量需求高的细胞过程，如蛋白质合成，以推动癌细胞生长和持续增殖。然而，致癌途径对这些关键过程的劫持会给细胞带来巨大的压力，必须通过适应性反应来减轻，以维持细胞存活。这些适应性反应是如何建立的，它们对肿瘤发展的功能后果，以及它们对治疗干预的意义在很大程度上仍然未知。我们使用前列腺癌（PCa）的鼠和人源化模型表明，未折叠蛋白反应的三个分支之一在晚期 PCa 中被选择性激活。这种适应性反应激活了真核起始因子 2-α 的磷酸化（P-eIF2α），将整体蛋白质合成重置到促进侵袭性肿瘤发展的水平，并且是在获得多个致癌病变后患者生存不良的标志物。使用患者来源的异种移植模型和 P-eIF2α 活性抑制剂 ISRIB，我们的数据表明，针对这种蛋白质合成的适应性刹车进行靶向治疗可以选择性地触发对侵袭性转移性 PCa 的细胞毒性，目前这种疾病尚无治愈方法。
