Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells

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...

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Veröffentlicht in:Endocrine-related cancer 2011-10, Vol.18 (5), p.541-554
Hauptverfasser: Di Florio, Alessia, Adesso, Laura, Pedrotti, Simona, Capurso, Gabriele, Pilozzi, Emanuela, Corbo, Vincenzo, Scarpa, Aldo, Geremia, Raffaele, Delle Fave, Gianfranco, Sette, Claudio
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container_end_page 554
container_issue 5
container_start_page 541
container_title Endocrine-related cancer
container_volume 18
creator Di Florio, Alessia
Adesso, Laura
Pedrotti, Simona
Capurso, Gabriele
Pilozzi, Emanuela
Corbo, Vincenzo
Scarpa, Aldo
Geremia, Raffaele
Delle Fave, Gianfranco
Sette, Claudio
description 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.
doi_str_mv 10.1530/ERC-10-0153
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection; Society for Endocrinology Journals
subjects Cell Adhesion - physiology
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Humans
Neuroendocrine Tumors - enzymology
Neuroendocrine Tumors - metabolism
Neuroendocrine Tumors - pathology
Pancreatic Neoplasms - enzymology
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Regular papers
RNA, Messenger - chemistry
RNA, Messenger - genetics
src-Family Kinases - metabolism
Tissue Array Analysis
TOR Serine-Threonine Kinases - metabolism
title Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells
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