Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Cell Cycle. 2013 Feb 1;12(3):522-32. doi: 10.4161/cc.23407. Epub 2013 Jan 16.
Mutant K-Ras and survivin both contribute to oncogenesis, but little is known about K-Ras requirement for the maintenance of the high levels of survivin in human tumors. Here we demonstrate that K-Ras depletion significantly decreases survivin levels in human cancer cells that harbor mutant but not wild type K-Ras. K-Ras depletion attenuates both basal and drug-induced survivin levels. The mechanism by which K-Ras depletion decreases survivin levels is through ubiquitination and proteasomal degradation of survivin and is independent of survivin-Thr-34 phosphorylation. Depletion of RalA and RalB, but not Raf-1, Akt1 and Akt2, decreases survivin levels, suggesting that K-Ras may regulate survivin stability through its RalGDS/Ral but not PI3K/Akt and Raf-1/Mek effector pathways. Furthermore, the ability of mutant K-Ras to induce anchorage-independent growth, invasion and survival is compromised by depletion of survivin. These studies suggest that mutant K-Ras contributes to the maintenance of the aberrantly high levels of survivin in tumors by regulating its stability, and that the ability of mutant K-Ras to induce malignant transformation is, at least in part, dependent on these high levels of survivin.
突变型 K-Ras 和 survivin 均有助于肿瘤发生，但对于 K-Ras 维持人类肿瘤中高水平 survivin 的作用知之甚少。本文中，我们证明在携带突变型而非野生型 K-Ras 的人类癌细胞中，K-Ras 的耗竭可显著降低 survivin 水平。K-Ras 的耗竭可减弱基础状态和药物诱导的 survivin 水平。K-Ras 耗竭降低 survivin 水平的机制是通过 survivin 的泛素化和蛋白酶体降解，且不依赖于 survivin-Thr-34 磷酸化。RalA 和 RalB 的耗竭（而非 Raf-1、Akt1 和 Akt2）可降低 survivin 水平，提示 K-Ras 可能通过其 RalGDS/Ral 而非 PI3K/Akt 和 Raf-1/Mek 效应途径调节 survivin 稳定性。此外，survivin 的耗竭削弱了突变型 K-Ras 诱导的非锚定依赖性生长、侵袭和存活的能力。这些研究提示，突变型 K-Ras 通过调节 survivin 的稳定性有助于维持肿瘤中异常高水平的 survivin，而突变型 K-Ras 诱导恶性转化的能力至少部分依赖于这些高水平的 survivin。
