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Epidermal growth factor receptor endocytic traffic perturbation by phosphatidate phosphohydrolase inhibition: new strategy against cancer.

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.
AuthorsRonan Shaughnessy, Claudio Retamal, Claudia Oyanadel, Andrés Norambuena, Alejandro López, Marcela Bravo-Zehnder, Fabian J Montecino, Claudia Metz, Andrea Soza, Alfonso González
JournalThe FEBS journal (FEBS J) Vol. 281 Issue 9 Pg. 2172-89 (May 2014) ISSN: 1742-4658 [Electronic] England
PMID24597955 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 FEBS.
Chemical References
  • Enzyme Inhibitors
  • Ligands
  • Propranolol
  • ErbB Receptors
  • Phosphatidate Phosphatase
  • Desipramine
Topics
  • Desipramine (pharmacology)
  • Endocytosis
  • Endosomes (drug effects, metabolism)
  • Enzyme Inhibitors (pharmacology, therapeutic use)
  • ErbB Receptors (metabolism)
  • HeLa Cells
  • Humans
  • Ligands
  • Neoplasms (drug therapy)
  • Phosphatidate Phosphatase (antagonists & inhibitors)
  • Phosphorylation
  • Propranolol (pharmacology)

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