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Impact of Mutational Status on Intracellular Effects of Cell‐Permeable CaaX Peptides in Pancreatic Cancer Cells
Author(s) -
Klußmann Merlin,
Matijass Martin,
Neundorf Ines
Publication year - 2025
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202401076
Subject(s) - kras , prenylation , biology , farnesyltransferase , pancreatic cancer , microbiology and biotechnology , palmitoylation , signal transduction , biochemistry , mutant , cancer research , chemistry , cancer , cysteine , mutation , gene , genetics , enzyme
Prenyltransferases add a lipid group to the cysteine of a CaaX motif of proteins. This posttranslational modification enables proteins to attach to membranes where they are essential hubs for signaling, trafficking, and apoptosis. Recently, cell‐permeable CaaX‐peptides are developed as possible tools to interfere with the prenylation machinery. These peptides cause cytotoxic effects, particularly in KRas mutant pancreatic cancer cells (PANC‐1) in which they also alter downstream signaling of Ras proteins. Herein, the aim is to get more clues about the relevance of the mutational status of KRas. Therefore, the activity of CaaX‐peptides in KRas wildtype BxPC‐3 and KRas mutated PANC‐1 cells is compared. CaaX‐peptides differently influence these two cell lines, although they internalize pretty much to the same extent. Indeed, an altered KRas plasma membrane localization in PANC‐1 cells is observed, probably induced by disturbed KRas prenylation based on the presence of CaaX‐peptides. The impact of CaaX‐peptides on KRas signaling is likely dependent on the KRas mutation in PANC‐1 cells in which they further trigger effects on KRas‐dependent regulators, e.g., Neurofibromin −1 (NF1) and son of sevenless homolog 1 (SOS1). All in all, CaaX peptides are identified as promising tools for studying and manipulating the function of therapeutically important prenylated proteins.

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