title: Mechanisms regulating cell membrane localization of the chemokine receptor CXCR4 in human hepatocarcinoma cells.
abstract: Hepatocellular carcinoma (HCC) cells with a mesenchymal phenotype show an asymmetric subcellular distribution of the chemokine receptor CXCR4, which is required for cell migration and invasion. In this work we examine the mechanisms that regulate the intracellular trafficking of CXCR4 in HCC cells. Results indicate that HCC cells present CXCR4 at the cell surface, but most of this protein is in endomembranes colocalizing with markers of the Golgi apparatus and recycling endosomes. The presence of high protein levels of CXCR4 present at the cell surface correlates with a mesenchymal-like phenotype and a high autocrine activation of the Transforming Growth Factor-beta (TGF-β) pathway. CXCR4 traffics along the Golgi/exocyst/plasma membrane pathway and requires EXOC4 (Sec8) component of the exocyst complex. HCC cells use distinct mechanisms for the CXCR4 internalization such as dynamin-dependent endocytosis and macropinocytosis. Regardless of the endocytic mechanisms, colocalization of CXCR4 and Rab11 is observed, which could be involved not only in receptor recycling but also in its post-Golgi transport. In summary, this work highlights membrane trafficking pathways whose pharmacological targeting could subsequently result in the inactivation of one of the main guiding mechanisms used by metastatic cells to colonize secondary organs and tissues.
authors.affiliation: Bellvitge Biomedical Research Institute (IDIBELL) L'Hospitalet, Barcelona, Spain.
authors.forename: Edgar B
authors.initials: EB
authors.lastname: Cepeda
authors.affiliation: Bellvitge Biomedical Research Institute (IDIBELL) L'Hospitalet, Barcelona, Spain.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Dediulia
authors.affiliation: Bellvitge Biomedical Research Institute (IDIBELL) L'Hospitalet, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Fernando
authors.affiliation: Bellvitge Biomedical Research Institute (IDIBELL) L'Hospitalet, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Bertran
authors.affiliation: University of Barcelona, School of Medicine, Barcelona Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Institut de Nanociències i Nanotecnologia (IN2UB).
authors.forename: Gustavo
authors.initials: G
authors.lastname: Egea
authors.affiliation: Bellvitge Biomedical Research Institute (IDIBELL) L'Hospitalet, Barcelona, Spain.
authors.forename: Estanislao
authors.initials: E
authors.lastname: Navarro
authors.affiliation: Bellvitge Biomedical Research Institute (IDIBELL) L'Hospitalet, Barcelona, Spain; University of Barcelona, School of Medicine, Barcelona Spain. Electronic address: ifabregat@idibell.cat.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fabregat
mesh_terms: D020126:Brefeldin A / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000494:pharmacology; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D010873:Pinocytosis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D033921:Vesicular Transport Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D020126:Brefeldin A
keywords: CXCR4; EXOC4; Exocyst; Hepatocellular carcinoma; Rab11; TGF-beta