title: Vitronectin-αvβ3 integrin engagement directs hypoxia-resistant mTOR activity and sustained protein synthesis linked to invasion by breast cancer cells.
abstract: The tumor microenvironment is a crucial player in the ability of cancer cells to acquire the ability to survive under the hypoxic environment and promote migration and invasion. Translational regulation is an essential part of cancer development and progression. Protein synthesis consumes considerable cellular metabolic energy and is therefore highly regulated, in turn controlling tumor cell proliferation and survival in extreme tumor-host conditions. Protein synthesis is typically downregulated by hypoxia, impairing cell proliferation and migration. Here, we show that breast cancer cells expressing integrin αvβ3, when engaging the extracellular matrix (ECM) protein vitronectin, strongly upregulate both mTOR activity and cap-dependent mRNA translation, which overrides their inhibition by hypoxia and facilitates tumor cell invasion. Interaction of vitronectin with integrin αvβ3 results in the continued activation of the kinase mTOR despite hypoxia through a mechanism that is dependent on integrin-linked kinase but is independent of focal adhesion kinase. Continuous activation of mTOR despite hypoxia involves release of translation initiation factor eIF4E from its repressor protein 4E-BP1, which is required for vitronectin-mediated tumor cell invasion. As integrin αvβ3 is associated with breast cancer cell invasion and metastasis to bone, we propose that the interaction with specific ECM proteins can influence cancer cell invasion, in part, by hyperactivation of mTOR, thereby promoting and sustaining protein synthesis under hypoxic conditions.
authors.affiliation: Department of Microbiology and Radiation Oncology, and NYU Cancer Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Pola
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Formenti
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schneider
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D018797:Cell Cycle Proteins; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D019096:Vitronectin / Q000235:genetics / Q000378:metabolism*; D000099200:Scaffold Protein ILK
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D039561:Eukaryotic Initiation Factor-4E; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D039302:Integrin alphaVbeta3; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019096:Vitronectin; D000099200:Scaffold Protein ILK; C087000:EIF4EBP1 protein, human; C546842:MTOR protein, human; C496050:PTK2 protein, human