Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Mol Cancer Ther. 2018 Dec;17(12):2622-2632. doi: 10.1158/1535-7163.MCT-18-0724. Epub 2018 Oct 3.
Pancreatic-type ribonucleases (ptRNases) are prevalent secretory enzymes that catalyze the cleavage of RNA. Ribonuclease inhibitor (RI) is a cytosolic protein that has femtomolar affinity for ptRNases, affording protection from the toxic catalytic activity of ptRNases, which can invade human cells. A human ptRNase variant that is resistant to inhibition by RI is a cytotoxin that is undergoing a clinical trial as a cancer chemotherapeutic agent. We find that the ptRNase and protein kinases in the ERK pathway exhibit strongly synergistic toxicity toward lung cancer cells (including a KRAS variant) and melanoma cells (including BRAF variants). The synergism arises from inhibiting the phosphorylation of RI and thereby diminishing its affinity for the ptRNase. These findings link seemingly unrelated cellular processes, and suggest that the use of a kinase inhibitor to unleash a cytotoxic enzyme could lead to beneficial manifestations in the clinic.
胰腺核糖核酸酶（ptRNases）是普遍存在的分泌酶，可催化 RNA 的切割。核糖核酸酶抑制剂（RI）是一种细胞溶质蛋白，对 ptRNases 具有飞摩尔亲和力，可防止 ptRNases 的毒性催化活性侵入人体细胞。一种对 RI 抑制具有抗性的人源 ptRNase 变体是一种细胞毒素，正在作为癌症化疗药物进行临床试验。我们发现，内质网中的 ptRNase 和蛋白激酶ERK 途径对肺癌细胞（包括 KRAS 变体）和黑色素瘤细胞（包括 BRAF 变体）表现出强烈的协同毒性。协同作用源于抑制 RI 的磷酸化，从而降低其与 ptRNase 的亲和力。这些发现将看似不相关的细胞过程联系起来，并表明使用激酶抑制剂释放细胞毒性酶可能会在临床上产生有益的表现。
