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Because endocytic trafficking is a crucial regulator of EGFR<\/jats:styled-content> function, its pharmacological perturbation might provide a new anti\u2010tumoral strategy. Inhibition of phosphatidic acid (PA<\/jats:styled-content>) phosphohydrolase (PAP<\/jats:styled-content>) activity has been shown to trigger PA<\/jats:styled-content> signaling towards type 4 phosphodiesterase (PDE<\/jats:styled-content>4) activation and protein kinase A<\/jats:styled-content> inhibition, leading to internalization of empty\/inactive EGFR<\/jats:styled-content>. Here, we used propranolol, its l<\/jats:sc>\u2010 and d<\/jats:sc>\u2010 isomers and desipramine as PAP<\/jats:styled-content> inhibitors to further explore the effects of PAP<\/jats:styled-content> inhibition on EGFR<\/jats:styled-content> endocytic trafficking and its consequences on EGFR<\/jats:styled-content>\u2010dependent cancer cell line models. PAP<\/jats:styled-content> inhibition not only made EGFR<\/jats:styled-content> inaccessible to stimuli but also prolonged the signaling lifetime of ligand\u2010activated EGFR<\/jats:styled-content> in recycling endosomes. Strikingly, such endocytic perturbations applied in acute\/intermittent PAP<\/jats:styled-content> inhibitor treatments selectively impaired cell proliferation\/viability sustained by an exaggerated EGFR<\/jats:styled-content> function. Phospholipase D<\/jats:styled-content> inhibition with FIPI (5\u2010fluoro\u20102\u2010indolyl des\u2010chlorohalopemide) and PDE<\/jats:styled-content>4 inhibition with rolipram abrogated both the anti\u2010tumoral and endocytic effects of PAP<\/jats:styled-content> inhibition. Prolonged treatments with a low concentration of PAP<\/jats:styled-content> inhibitors, although without detectable endocytic effects, still counteracted cell proliferation, induced apoptosis and decreased anchorage\u2010independent growth of cells bearing EGFR<\/jats:styled-content> oncogenic influences. Overall, our results show that PAP<\/jats:styled-content> inhibitors can counteract EGFR<\/jats:styled-content> oncogenic traits, including receptor overexpression or activating mutations resistant to current tyrosine kinase inhibitors, perturbing EGFR<\/jats:styled-content> endocytic trafficking and perhaps other as yet unknown processes, depending on treatment conditions. This puts PAP<\/jats:styled-content> activity forward as a new suitable target against EGFR<\/jats:styled-content>\u2010driven malignancy.<\/jats:p>","DOI":"10.1111\/febs.12770","type":"journal-article","created":{"date-parts":[[2014,3,6]],"date-time":"2014-03-06T07:41:40Z","timestamp":1394091700000},"page":"2172-2189","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Epidermal growth factor receptor endocytic traffic perturbation by phosphatidate phosphohydrolase inhibition: new strategy against cancer"],"prefix":"10.1111","volume":"281","author":[{"given":"Ronan","family":"Shaughnessy","sequence":"first","affiliation":[{"name":"Departamento de Inmunolog\u00eda Cl\u00ednica y Reumatolog\u00eda Facultad de Medicina Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"},{"name":"Centro de Envejecimiento y Regeneraci\u00f3n Departamento de Biolog\u00eda Celular y Molecular Facultad de Ciencias 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