Down-regulation of PAR1 activity with a pHLIP-based allosteric antagonist induces cancer cell death
Kelly E Burns1, Damien Thévenin2
1Department of Chemistry, Lehigh University, 6 East Packer Ave, Bethlehem, PA 18015, U.S.A.
Abstract:
Even though abnormal expression of G protein-coupled receptors (GPCRs) and of their ligands is observed in many cancer cells of various origins, only a few anti-cancer compounds directly act on their signalling. One promising approach to modulate their activity consists of targeting the receptor cytoplasmic surfaces interacting with the associated G-proteins using peptides mimicking the intracellular loops of the receptor. Thus, to be fully effective, the peptide mimics must be selectively targeted to the tumour while sparing healthy tissues, translocated across the cell membrane and stay anchored to the cytoplasmic leaflet of the plasma membrane. In the present study, we introduce a novel way to selectively target and inhibit the activity of a GPCR in cancer cells under acidic conditions, such as those found in solid tumours. We find that the conjugation of a peptide fragment derived from the third intracellular loop (i3) of the protease-activated receptor 1 (PAR1) to a peptide that can selectively target tumours solely based on their acidity [pH(Low) Insertion Peptide (pHLIP)], produces a construct capable of effectively down-regulating PAR1 activity in a concentration- and pH-dependent manner and of inducing a potent cytotoxic effect in a panel of cancer cells that is proportional to the relative level of receptor expression at the cell surface. This strategy not only allows for a more selective targeting and specific intracellular delivery than current approaches, but also offers new possibilities for developing novel anti-cancer drugs targeting GPCRs.
Insights
Researchers developed a novel peptide construct that targets G protein-coupled receptors (GPCRs) in cancer cells by exploiting tumor acidity. This targeted approach effectively inhibits GPCR activity and induces cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Abnormal expression of G protein-coupled receptors (GPCRs) and their ligands is common in various cancers.
- Current anti-cancer therapies rarely target GPCR signaling directly.
- Modulating GPCR activity via peptide mimics of intracellular loops is a promising strategy.
Purpose of the Study:
- To develop a novel method for selectively targeting and inhibiting GPCR activity in cancer cells under acidic tumor conditions.
- To create a peptide construct that leverages tumor-specific acidity for targeted delivery and inhibition.
Main Methods:
- Conjugation of a protease-activated receptor 1 (PAR1) third intracellular loop (i3) peptide fragment with a pH-Low Insertion Peptide (pHLIP).
- Evaluation of the construct's ability to down-regulate PAR1 activity in cancer cells.
- Assessment of the construct's pH- and concentration-dependent effects.
- Analysis of the cytotoxic effect on cancer cells in relation to PAR1 expression levels.
Main Results:
- The novel peptide construct effectively down-regulates PAR1 activity in a concentration- and pH-dependent manner.
- The construct selectively targets cancer cells in acidic environments, such as solid tumors.
- A potent cytotoxic effect was observed in cancer cells, proportional to cell surface PAR1 expression.
- This strategy offers improved tumor targeting and intracellular delivery compared to existing methods.
Conclusions:
- The developed peptide construct provides a novel and selective approach to inhibit GPCRs in cancer cells by utilizing tumor acidity.
- This strategy enhances targeted delivery and intracellular penetration, offering new avenues for anti-cancer drug development.
- The findings suggest a promising therapeutic strategy for cancers characterized by abnormal GPCR expression and acidic microenvironments.
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