Cell‐permeable CaaX‐peptides affect K‐Ras downstream signaling and promote cell death in cancer cells

Cell‐permeable peptides bearing a C‐terminal CaaX motif based on Ras sequences are introduced. We highlight intracellular accumulation of those peptides, which is controlled by the presence of their CaaX motif, and their specific interaction with intracellular prenyltransferases. As proof of concept, we further show their utilization to alter downstream signaling of K‐Ras‐4B in pancreatic cancer cells. Application of this strategy holds great promise to better understand and regulate post‐translational cysteine prenylation. Cysteine prenylation is a post‐translational modification that is used by nature to control crucial biological functions of proteins, such as membrane trafficking, signal transduction, and apoptosis. It mainly occurs in eukaryotic proteins at a C‐terminal CaaX box and is mediated by prenyltransferases. Since the discovery of prenylated proteins, various tools have been developed to study the mechanisms of prenyltransferases, as well as to visualize and to identify prenylated proteins. Herein, we introduce cell‐permeable peptides bearing a C‐terminal CaaX motif based on Ras sequences. We demonstrate that intracellular accumulation of those peptides in different cells is controlled by the presence of their CaaX motif and that they specifically interact with intracellular prenyltransferases. As proof of concept, we further highlight their utilization to alter downstream signaling of Ras proteins, particularly of K‐Ras‐4B, in pancreatic cancer cells. Application of this strategy holds great promise to better understand and regulate post‐translational cysteine prenylation.