title: Hydroxytyrosol, a product from olive oil, reduces colon cancer growth by enhancing epidermal growth factor receptor degradation.
abstract: METHODS
  We studied the effects and mechanism of 2-(3,4-dihydroxyphenil)ethanol (or hydroxytyrosol, HT), a polyphenol from extra virgin olive oil, investigating the regulation of epidermal growth factor receptor (EGFR) expression in colon tumour cells.
  
  
  RESULTS
  We demonstrate that HT significantly downregulates EGFR expression in human colorectal adenocarcinoma cells HT-29, CaCo2, and WiDr, and in HT-29 xenografts. HT accelerates EGFR degradation by reducing its half-life. Specifically, HT induces EGFR ubiquitination that is mediated by phosphorylation at pY1045, the docking site for Cbl, thereby enabling receptor ubiquitination and degradation. Pretreatment with either the lysosomal inhibitor chloroquine, or the proteasomal inhibitor MG132 blocks HT-induced EGFR downregulation. In colon cancer cells, EGFR downregulation by HT is associated with reduced cell proliferation. Tumour growth and EGFR expression levels are also decreased by HT treatment in HT-29 xenograft.
  
  
  CONCLUSIONS
  We conclude that HT downregulates EGFR expression via lysosomal and proteasomal degradation, activated by HT-induced EGFR phosphorylation at pY1045 and increased Cbl activity. Cbl activation induces, in turn, EGFR ubiquitination. Our results reveal a new mechanism for HT's antitumour effects that may be important for colon tumour prevention and treatment.
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Terzuoli
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giachetti
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.|Istituto Toscano Tumori (ITT), Florence, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ziche
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.|Istituto Toscano Tumori (ITT), Florence, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donnini
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D019073:HT29 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008819:Mice, Nude; D000069463:Olive Oil / Q000737:chemistry*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000069463:Olive Oil; C005975:3,4-dihydroxyphenylethanol; D014443:Tyrosine; C512478:EGFR protein, human; D066246:ErbB Receptors; D046988:Proteasome Endopeptidase Complex; D010626:Phenylethyl Alcohol
keywords: Colon cancer; EGFR degradation; Hydroxytyrosol; Olive oil; Polyphenols