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

Klimpel, Annika; Stillger, Katharina; Wiederstein, Janica L.; Krüger, Marcus; Neundorf, Ines

doi:10.1111/febs.15612

Cited by 12 publications

(18 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The sequences of TAT and Antennapedia (Antp) are RKKRRQRRRP and RQIKIWFQNRRMKWKK, respectively, and the sequence of the TM4SF5 C-terminus is 187 GDCRKKQDTPH 197 . The sequence of the Caax motif is CVIM, and it was conjugated between the TAT and TM4SF5 C-terminal sequences to avoid structural interference of the short TM4SF5 C-terminus, presumably without any secondary structure, although the Caax sequence is conjugated to the end of K-Ras for the cell-penetrating effects [26]. Peptides were maintained at 1 mM for stock solutions in PBS and then diluted into culture media containing 10% FBS prior to treating the cells at different concentrations or conditions.…”

Section: Methodsmentioning

confidence: 99%

N-terminus-independent activation of c-Src via binding to a tetraspan(in) TM4SF5 in hepatocellular carcinoma is abolished by the TM4SF5 C-terminal peptide application

Song¹,

Lee²,

Kim³

et al. 2021

Theranostics

View full text Add to dashboard Cite

Active c-Src non-receptor tyrosine kinase localizes to the plasma membrane via N-terminal lipid modification. Membranous c-Src causes cancer initiation and progression. Even though transmembrane 4 L six family member 5 (TM4SF5), a tetraspan(in), can be involved in this mechanism, the molecular and structural influence of TM4SF5 on c-Src remains unknown. Methods: Here, we investigated molecular and structural details by which TM4SF5 regulated c-Src devoid of its N-terminus and how cell-penetrating peptides were able to interrupt c-Src activation via interference of c-Src-TM4SF5 interaction in hepatocellular carcinoma models. Results: The TM4SF5 C-terminus efficiently bound the c-Src SH1 kinase domain, efficiently to the inactively-closed form. The complex involved protein tyrosine phosphatase 1B able to dephosphorylate Tyr530. The c-Src SH1 domain alone, even in a closed form, bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation. Homology modeling and molecular dynamics simulation studies predicted the directly interfacing residues, which were further validated by mutational studies. Cell penetration of TM4SF5 C-terminal peptides blocked the interaction of TM4SF5 with c-Src and prevented c-Src-dependent tumor initiation and progression in vivo. Conclusions: Collectively, these data demonstrate that binding of the TM4SF5 C-terminus to the kinase domain of inactive c-Src leads to its activation. Because this binding can be abolished by cell-penetrating peptides containing the TM4SF5 C-terminus, targeting this direct interaction may be an effective strategy for developing therapeutics that block the development and progression of hepatocellular carcinoma.

show abstract

Section: Methodsmentioning

confidence: 99%

N-terminus-independent activation of c-Src via binding to a tetraspan(in) TM4SF5 in hepatocellular carcinoma is abolished by the TM4SF5 C-terminal peptide application

Song¹,

Lee²,

Kim³

et al. 2021

Theranostics

View full text Add to dashboard Cite

show abstract

“…As FTase’s recognize, modifiy and activate cysteine residues at the carbonyl terminus of the tetrapeptide (CaaX) and catalyze the covalent link of a farnesyl group [ 35 ], Dumitriu et al (2015) designed CaaX competitive inhibitors, by modification of the phenothiazine scaffold by introducing aminoacids, to synthesize zinc chelating compounds. These phenothiazine derivatives were prepared by combination with cysteine, methionine, serine, and valine residues.…”

Section: Anticancer Hybridsmentioning

confidence: 99%

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review

et al. 2022

View full text Add to dashboard Cite

The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity.

show abstract

“…In 2020, Klimpel et al developed a construct containing a C-terminal CaaX motif based on Ras sequences named as sC18*-KRas4B (GLRKRLRKFRNK-SKTK-CVIM). This construct exhibited intracellular accumulation, interacting with intracellular prenyltransferases which leads to downstream signaling of Ras proteins in pancreatic cancer cells [ 138 ]. Several other therapeutic cyclic CPPs have been reported which target the Ras superfamily.…”

Section: Delivery Of Proteins/peptidesmentioning

confidence: 99%

Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade

et al. 2021

View full text Add to dashboard Cite

Cell-penetrating peptides (CPPs), also known as protein transduction domains, are a class of diverse amino acid sequences with the ability to cross cellular membranes. CPPs can deliver several bioactive cargos, including proteins, peptides, nucleic acids and chemotherapeutics, into cells. Ever since their discovery, synthetic and natural CPPs have been utilized in therapeutics delivery, gene editing and cell imaging in fundamental research and clinical experiments. Over the years, CPPs have gained significant attention due to their low cytotoxicity and high transduction efficacy. In the last decade, multiple investigations demonstrated the potential of CPPs as carriers for the delivery of therapeutics to treat various types of cancer. Besides their remarkable efficacy owing to fast and efficient delivery, a crucial benefit of CPP-based cancer treatments is delivering anticancer agents selectively, rather than mediating toxicities toward normal tissues. To obtain a higher therapeutic index and to improve cell and tissue selectivity, CPP-cargo constructions can also be complexed with other agents such as nanocarriers and liposomes to obtain encouraging outcomes. This review summarizes various types of CPPs conjugated to anticancer cargos. Furthermore, we present a brief history of CPP utilization as delivery systems for anticancer agents in the last decade and evaluate several reports on the applications of CPPs in basic research and preclinical studies.

show abstract

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

Abstract: access funding enabled and organized by ProjektDEAL.

Cited by 12 publications

References 80 publications

N-terminus-independent activation of c-Src via binding to a tetraspan(in) TM4SF5 in hepatocellular carcinoma is abolished by the TM4SF5 C-terminal peptide application

N-terminus-independent activation of c-Src via binding to a tetraspan(in) TM4SF5 in hepatocellular carcinoma is abolished by the TM4SF5 C-terminal peptide application

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review

Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade

Contact Info

Product

Resources

About