title: Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells.
abstract: Pancreatic endocrine tumours (PETs) are rare and heterogeneous neoplasms, often diagnosed at metastatic stage, for which no cure is currently available. Recently, activation of two pathways that support proliferation and invasiveness of cancer cells, the Src family kinase (SFK) and mammalian target of rapamycin (mTOR) pathways, was demonstrated in PETs. Since both pathways represent suitable targets for therapeutic intervention, we investigated their possible interaction in PETs. Western blot and immunofluorescence analyses indicated that SFK and mTOR activity correlate in PET cell lines. We also found that SFKs coordinate cell adhesion and spreading with activation of the mTOR pathway in PET cells. Live cell metabolic labelling and biochemical studies demonstrated that SFK activity enhance mTOR-dependent translation initiation. Furthermore, microarray analysis of the mRNAs associated with polyribosomes revealed that SFKs regulate mTOR-dependent translation of specific transcripts, with an enrichment in mRNAs encoding cell cycle proteins. Importantly, a synergic inhibition of proliferation was observed in PET cells concomitantly treated with SFK and mTOR inhibitors, without activation of the phosphatidylinositol 3-kinase/AKT pro-survival pathway. Tissue microarray analysis revealed activation of Src and mTOR in some PET samples, and identified phosphorylation of 4E-BP1 as an independent marker of poor prognosis in PETs. Thus, our work highlights a novel link between the SFK and mTOR pathways, which regulate the translation of mRNAs for cell cycle regulators, and suggest that crosstalk between these pathways promotes PET cell proliferation.
authors.affiliation: Department of Public Health and Cell Biology, University of Rome Tor Vergata, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Di Florio
authors.forename: Laura
authors.initials: L
authors.lastname: Adesso
authors.forename: Simona
authors.initials: S
authors.lastname: Pedrotti
authors.forename: Gabriele
authors.initials: G
authors.lastname: Capurso
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pilozzi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Corbo
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Raffaele
authors.initials: R
authors.lastname: Geremia
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Delle Fave
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
mesh_terms: D002448:Cell Adhesion / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D018358:Neuroendocrine Tumors / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D012333:RNA, Messenger; C546842:MTOR protein, human; D019061:src-Family Kinases; D058570:TOR Serine-Threonine Kinases