Epidermal growth factor receptor endocytic traffic perturbation by phosphatidate phosphohydrolase inhibition: new
Ronan Shaughnessy1, Claudio Retamal, Claudia Oyanadel
1Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Abstract:
Epidermal growth factor receptor (EGFR) exaggerated (oncogenic) function is currently targeted in cancer treatment with drugs that block receptor ligand binding or tyrosine kinase activity. Because endocytic trafficking is a crucial regulator of EGFR function, its pharmacological perturbation might provide a new anti-tumoral strategy. Inhibition of phosphatidic acid (PA) phosphohydrolase (PAP) activity has been shown to trigger PA signaling towards type 4 phosphodiesterase (PDE4) activation and protein kinase A inhibition, leading to internalization of empty/inactive EGFR. Here, we used propranolol, its l- and d- isomers and desipramine as PAP inhibitors to further explore the effects of PAP inhibition on EGFR endocytic trafficking and its consequences on EGFR-dependent cancer cell line models. PAP inhibition not only made EGFR inaccessible to stimuli but also prolonged the signaling lifetime of ligand-activated EGFR in recycling endosomes. Strikingly, such endocytic perturbations applied in acute/intermittent PAP inhibitor treatments selectively impaired cell proliferation/viability sustained by an exaggerated EGFR function. Phospholipase D inhibition with FIPI (5-fluoro-2-indolyl des-chlorohalopemide) and PDE4 inhibition with rolipram abrogated both the anti-tumoral and endocytic effects of PAP inhibition. Prolonged treatments with a low concentration of PAP inhibitors, although without detectable endocytic effects, still counteracted cell proliferation, induced apoptosis and decreased anchorage-independent growth of cells bearing EGFR oncogenic influences. Overall, our results show that PAP inhibitors can counteract EGFR oncogenic traits, including receptor overexpression or activating mutations resistant to current tyrosine kinase inhibitors, perturbing EGFR endocytic trafficking and perhaps other as yet unknown processes, depending on treatment conditions. This puts PAP activity forward as a new suitable target against EGFR-driven malignancy.
Insights
Inhibiting phosphatidic acid phosphohydrolase (PAP) disrupts epidermal growth factor receptor (EGFR) trafficking, offering a novel cancer therapy. This approach targets exaggerated EGFR function, even in resistant cases.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Exaggerated epidermal growth factor receptor (EGFR) signaling drives cancer.
- Current treatments target EGFR ligand binding or kinase activity.
- EGFR endocytic trafficking is a critical regulator of its function.
Purpose of the Study:
- To investigate phosphatidic acid phosphohydrolase (PAP) inhibition as an anti-tumoral strategy.
- To explore the effects of PAP inhibition on EGFR endocytic trafficking.
- To evaluate PAP inhibitors in EGFR-dependent cancer models.
Main Methods:
- Utilized propranolol isomers and desipramine as PAP inhibitors.
- Examined EGFR endocytic trafficking and signaling.
- Assessed cell proliferation, viability, apoptosis, and anchorage-independent growth.
- Used phospholipase D (FIPI) and PDE4 (rolipram) inhibitors to confirm mechanisms.
Main Results:
- PAP inhibition altered EGFR trafficking, reducing accessibility to stimuli.
- Ligand-activated EGFR signaling lifetime in recycling endosomes was prolonged.
- Acute PAP inhibition impaired proliferation and viability in EGFR-driven cancer cells.
- Prolonged low-dose PAP inhibition also reduced proliferation and induced apoptosis.
- FIPI and rolipram abrogated PAP inhibitor effects, confirming the pathway.
Conclusions:
- PAP inhibitors represent a novel therapeutic strategy against EGFR-driven malignancies.
- PAP inhibition perturbs EGFR endocytic trafficking and other processes.
- This approach is effective against EGFR overexpression and mutations resistant to TKIs.
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