Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China
Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4158-4168. doi: 10.1073/pnas.1917938117. Epub 2020 Feb 12.
Cancer cells display novel characteristics which can be exploited for therapeutic advantage. Isolated studies have shown that 1) the mevalonate pathway and 2) increased macropinocytosis are important in tumorigenesis, but a connection between these two observations has not been envisioned. A library screen for compounds that selectively killed cells identified pitavastatin. Pitavastatin also killed human breast epithelial MCF10A cells lacking PTEN or expressing K-Ras, as well as mouse tumor organoids. The selective killing of cells with oncogenic defects was traced to GGPP (geranylgeranyl diphosphate) depletion. Disruption of GGPP synthase in revealed that GGPP is needed for pseudopod extension and macropinocytosis. Fluid-phase uptake through macropinocytosis is lower in PTEN-deleted cells and, as reported previously, higher in cells expressing activated Ras. Nevertheless, uptake was more sensitive to pitavastatin in cells with either of these oncogenic mutations than in wild-type cells. Loading the residual macropinosomes after pitavastatin with high concentrations of protein mitigated the cell death, indicating that defective macropinocytosis leads to amino acid starvation. Our studies suggest that the dependence of cancer cells on the mevalonate pathway is due to the role of GGPP in macropinocytosis and the reliance of these cells on macropinocytosis for nutrient uptake. Thus, inhibition of the networks mediating these processes is likely to be effective in cancer intervention.
癌细胞表现出新颖的特征，这些特征可被利用来获得治疗优势。孤立的研究表明，1）甲羟戊酸途径和 2）增加巨胞饮作用在肿瘤发生中很重要，但这两个观察结果之间的联系尚未被设想。用于选择性杀死 细胞的化合物文库筛选鉴定出了匹伐他汀。匹伐他汀还能杀死缺乏 PTEN 或表达 K-Ras 的人乳腺上皮 MCF10A 细胞，以及小鼠肿瘤类器官。具有致癌缺陷的细胞的选择性杀伤可追溯到 GGPP（香叶基香叶基二磷酸）耗竭。在 中破坏 GGPP 合酶表明 GGPP 是假足延伸和巨胞饮所必需的。通过巨胞饮摄取的液相摄取在 PTEN 缺失的细胞中较低，并且如先前报道的，在表达激活的 Ras 的细胞中较高。然而，在具有这些致癌突变中的任一种的细胞中，摄取对匹伐他汀的敏感性比在野生型细胞中更高。在用高浓度蛋白质装载匹伐他汀处理后的残余巨胞饮体可减轻细胞死亡，表明有缺陷的巨胞饮作用导致氨基酸饥饿。我们的研究表明，癌细胞对甲羟戊酸途径的依赖性是由于 GGPP 在巨胞饮作用中的作用以及这些细胞对巨胞饮作用摄取营养物质的依赖。因此，抑制介导这些过程的网络可能在癌症干预中有效。
