Laboratory for Pediatric Sarcoma Biology, Institute of Pathology of the LMU Munich, Munich, Germany.
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Oncogene. 2016 Sep 8;35(36):4675-88. doi: 10.1038/onc.2015.515. Epub 2016 Feb 1.
Protein synthesis activity is abnormally enhanced in cancer cells to support their uncontrolled growth. However, this process needs to be tightly restricted under metabolic stress-a condition often found within the tumor microenvironment-to preserve cell viability. mTORC1 is critical to link protein synthesis activity to nutrient and oxygen levels, in part by controlling the 4E-BP1-eIF4E axis. Whereas mTORC1 and eIF4E are known pro-tumorigenic factors, whose expression or activity is increased in numerous cancers, the role of 4E-BP1 in cancer is not yet definitive. On the one hand, 4E-BP1 has tumor suppressor activity by inhibiting eIF4E and, thus, blocking mRNA translation and proliferation. This is corroborated by elevated levels of phosphorylated and hence inactive 4E-BP1, which are detected in various cancers. On the other hand, 4E-BP1 has pro-tumorigenic functions as it promotes tumor adaptation to metabolic and genotoxic stress by selectively enhancing or preventing the translation of specific transcripts. Here we describe the molecular and cellular functions of 4E-BP1 and highlight the distinct roles of 4E-BP1 in cancer depending on the microenvironmental context of the tumor.
蛋白质合成活性在癌细胞中异常增强，以支持其不受控制的生长。然而，在代谢应激下（肿瘤微环境中经常存在的条件），这个过程需要受到严格限制，以维持细胞活力。mTORC1 对于将蛋白质合成活性与营养和氧气水平联系起来至关重要，部分是通过控制 4E-BP1-eIF4E 轴来实现的。虽然 mTORC1 和 eIF4E 是已知的促癌因素，它们在许多癌症中表达或活性增加，但 4E-BP1 在癌症中的作用尚不确定。一方面，4E-BP1 通过抑制 eIF4E 具有肿瘤抑制活性，从而阻止 mRNA 翻译和增殖。这一点得到了各种癌症中检测到的磷酸化（即失活）4E-BP1 水平升高的证实。另一方面，4E-BP1 具有促癌作用，因为它通过选择性增强或阻止特定转录本的翻译，促进肿瘤对代谢和遗传毒性应激的适应。在这里，我们描述了 4E-BP1 的分子和细胞功能，并强调了 4E-BP1 在癌症中的不同作用取决于肿瘤的微环境背景。
