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

被引:28
作者
Di Florio, Alessia [1 ,2 ,3 ]
Adesso, Laura [1 ,2 ,3 ]
Pedrotti, Simona [1 ,2 ]
Capurso, Gabriele [3 ]
Pilozzi, Emanuela [4 ]
Corbo, Vincenzo [5 ,6 ]
Scarpa, Aldo [5 ,6 ]
Geremia, Raffaele [1 ]
Delle Fave, Gianfranco [3 ]
Sette, Claudio [1 ,2 ]
机构
[1] Univ Roma Tor Vergata, Dept Publ Hlth & Cell Biol, I-00133 Rome, Italy
[2] CERC Fdn Santa Lucia, Lab Neuroembryol, Rome, Italy
[3] Univ Roma La Sapienza, Sch Med 2, Digest & Liver Dis Unit, Rome, Italy
[4] Univ Roma La Sapienza, Sch Med 2, Dept Clin & Mol Med, Rome, Italy
[5] Univ Hosp Verona, ARC NET Res Ctr, Verona, Italy
[6] Univ Hosp Verona, Dept Pathol, Verona, Italy
关键词
CAP-DEPENDENT TRANSLATION; TYROSINE KINASES; CANCER; EXPRESSION; AKT; RECEPTOR; PHOSPHORYLATION; ASSOCIATION; DOWNSTREAM; EVEROLIMUS;
D O I
10.1530/ERC-10-0153
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. Endocrine-Related Cancer (2011) 18 541-554
引用
收藏
页码:541 / 554
页数:14
相关论文
共 38 条
  • [1] 4E-Binding protein 1:: A key molecular "Funnel factor" in human cancer with clinical implications
    Armengol, Gemma
    Rojo, Federico
    Castellvi, Josep
    Iglesias, Carmela
    Cuatrecasas, Miriam
    Pons, Berta
    Baselga, Jose
    Ramon y Cajal, Santiago
    [J]. CANCER RESEARCH, 2007, 67 (16) : 7551 - 7555
  • [2] When translation meets transformation: the mTOR story
    Averous, J.
    Proud, C. G.
    [J]. ONCOGENE, 2006, 25 (48) : 6423 - 6435
  • [3] The selectivity of protein kinase inhibitors: a further update
    Bain, Jenny
    Plater, Lorna
    Elliott, Matt
    Shpiro, Natalia
    Hastie, C. James
    Mclauchlan, Hilary
    Klevernic, Iva
    Arthur, J. Simon C.
    Alessi, Dario R.
    Cohen, Philip
    [J]. BIOCHEMICAL JOURNAL, 2007, 408 : 297 - 315
  • [4] Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells
    Bianchini, Andrea
    Loiarro, Maria
    Bielli, Pamela
    Busa, Roberta
    Paronetto, Maria Paola
    Loreni, Fabrizio
    Geremia, Raffaele
    Sette, Claudio
    [J]. CARCINOGENESIS, 2008, 29 (12) : 2279 - 2288
  • [5] The interplay between Src family kinases and receptor tyrosine kinases
    Bromann, PA
    Korkaya, H
    Courtneidge, SA
    [J]. ONCOGENE, 2004, 23 (48) : 7957 - 7968
  • [6] Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets
    Capurso, G.
    Lattimore, S.
    Crnogorac-Jurcevic, T.
    Panzuto, F.
    Milione, M.
    Bhakta, V.
    Campanini, N.
    Swift, S. M.
    Bord, C.
    Delle Fave, G.
    Lemoine, N. R.
    [J]. ENDOCRINE-RELATED CANCER, 2006, 13 (02) : 541 - 558
  • [7] Molecular target therapy for gastroenteropancreatic endocrine tumours: Biological rationale and clinical perspectives
    Capurso, Gabriele
    Fazio, Nicola
    Festa, Stefano
    Panzuto, Francesco
    De Braud, Filippo
    Delle Fave, Gianfranco
    [J]. CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, 2009, 72 (02) : 110 - 124
  • [8] Src family kinase activity regulates adhesion, spreading and migration of pancreatic endocrine tumour cells
    Di Florio, Alessia
    Capurso, Gabriele
    Milione, Massimo
    Panzuto, Francesco
    Geremia, Raffaele
    Delle Fave, Gianfranco
    Sette, Claudio
    [J]. ENDOCRINE-RELATED CANCER, 2007, 14 (01) : 111 - 124
  • [9] Changing incidence of pancreatic neoplasms - A 16-year review of statewide tumor registry
    Fitzgerald, Timothy L.
    Hickner, Zach J.
    Schmitz, Matthew
    Kort, Eric J.
    [J]. PANCREAS, 2008, 37 (02) : 134 - 138
  • [10] V-SRC'S hold over actin and cell adhesions
    Frame, MC
    Fincham, VJ
    Carragher, NO
    Wyke, JA
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2002, 3 (04) : 233 - 245