eIF6 over-expression increases the motility and invasiveness of cancer cells by modulating the expression of a critical subset of membrane-bound proteins

Michela Pinzaglia, Claudia Montaldo, Dorina Polinari, Mattei Simone, Anna La Teana, Marco Tripodi, Carmine Mancone, Paola Londei, Dario Benelli

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Eukaryotic Initiation factor 6 (eIF6) is a peculiar translation initiation factor that binds to the large 60S ribosomal subunits, controlling translation initiation and participating in ribosome biogenesis. In the past, knowledge about the mechanisms adopted by the cells for controlling protein synthesis by extracellular stimuli has focused on two translation initiation factors (eIF4E and eIF2), however, recent data suggest eIF6 as a newcomer in the control of downstream of signal transduction pathways. eIF6 is over-expressed in tumors and its decreased expression renders cells less prone to tumor growth. A previous work from our laboratory has disclosed that over-expression of eIF6 in transformed cell lines markedly increased cell migration and invasion. Methods: Here, we performed a quantitative proteomic analysis of membrane-associated proteins in A2780 ovarian cancer cells over-expressing eIF6. Differentially expressed proteins upon eIF6 overproduction were further investigated in silico by Ingenuity Pathway Analysis (IPA). RT-qPCR and Western blot were performed in order to validate the proteomic data. Furthermore, the effects of a potent and selective inhibitor ML-141 in A2780 cells were evaluated using transwell migration assay. Finally, we explored the effects of eIF6 over-expression on WM793 primary melanoma cell lines. Results: We demonstrated that: (i) the genes up-regulated upon eIF6 overproduction mapped to a functional network corresponding to cellular movements in a highly significant way; (ii) cdc42 plays a pivotal role as an effector of enhanced migratory phenotype induced upon eIF6 over-expression; (iii) the variations in abundance observed for cdc42 protein occur at a post-transcriptional level; (iv) the increased cell migration/invasion upon eIF6 over-expression was generalizable to other cell line models. Conclusions: Collectively, our data confirm and further extend the role of eIF6 in enhancing cell migration/invasion. We show that a number of membrane-associated proteins indeed vary in abundance upon eIF6 over-expression, and that the up-regulated proteins can be located within a functional network controlling cell motility and tumor metastasis. Full understanding of the role eIF6 plays in the metastatic process is important, also in view of the fact that this factor is a potentially druggable target to be exploited for new anti-cancer therapies.

Original languageEnglish
Article number131
JournalBMC Cancer
Volume15
Issue number1
DOIs
Publication statusPublished - Mar 15 2015

Fingerprint

Membrane Proteins
Neoplasms
Cell Movement
Peptide Initiation Factors
eIF-6
Proteomics
cdc42 GTP-Binding Protein
Eukaryotic Large Ribosome Subunits
Large Ribosome Subunits
Cell Line
Transformed Cell Line
Proteins
Ribosomes
Computer Simulation
Ovarian Neoplasms
Melanoma
Signal Transduction
Western Blotting
Neoplasm Metastasis
Phenotype

Keywords

  • cdc42
  • Cell migration
  • eIF6
  • Protein synthesis
  • Ribosome biogenesis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

eIF6 over-expression increases the motility and invasiveness of cancer cells by modulating the expression of a critical subset of membrane-bound proteins. / Pinzaglia, Michela; Montaldo, Claudia; Polinari, Dorina; Simone, Mattei; La Teana, Anna; Tripodi, Marco; Mancone, Carmine; Londei, Paola; Benelli, Dario.

In: BMC Cancer, Vol. 15, No. 1, 131, 15.03.2015.

Research output: Contribution to journalArticle

Pinzaglia, Michela ; Montaldo, Claudia ; Polinari, Dorina ; Simone, Mattei ; La Teana, Anna ; Tripodi, Marco ; Mancone, Carmine ; Londei, Paola ; Benelli, Dario. / eIF6 over-expression increases the motility and invasiveness of cancer cells by modulating the expression of a critical subset of membrane-bound proteins. In: BMC Cancer. 2015 ; Vol. 15, No. 1.
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AU - Montaldo, Claudia

AU - Polinari, Dorina

AU - Simone, Mattei

AU - La Teana, Anna

AU - Tripodi, Marco

AU - Mancone, Carmine

AU - Londei, Paola

AU - Benelli, Dario

PY - 2015/3/15

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N2 - Background: Eukaryotic Initiation factor 6 (eIF6) is a peculiar translation initiation factor that binds to the large 60S ribosomal subunits, controlling translation initiation and participating in ribosome biogenesis. In the past, knowledge about the mechanisms adopted by the cells for controlling protein synthesis by extracellular stimuli has focused on two translation initiation factors (eIF4E and eIF2), however, recent data suggest eIF6 as a newcomer in the control of downstream of signal transduction pathways. eIF6 is over-expressed in tumors and its decreased expression renders cells less prone to tumor growth. A previous work from our laboratory has disclosed that over-expression of eIF6 in transformed cell lines markedly increased cell migration and invasion. Methods: Here, we performed a quantitative proteomic analysis of membrane-associated proteins in A2780 ovarian cancer cells over-expressing eIF6. Differentially expressed proteins upon eIF6 overproduction were further investigated in silico by Ingenuity Pathway Analysis (IPA). RT-qPCR and Western blot were performed in order to validate the proteomic data. Furthermore, the effects of a potent and selective inhibitor ML-141 in A2780 cells were evaluated using transwell migration assay. Finally, we explored the effects of eIF6 over-expression on WM793 primary melanoma cell lines. Results: We demonstrated that: (i) the genes up-regulated upon eIF6 overproduction mapped to a functional network corresponding to cellular movements in a highly significant way; (ii) cdc42 plays a pivotal role as an effector of enhanced migratory phenotype induced upon eIF6 over-expression; (iii) the variations in abundance observed for cdc42 protein occur at a post-transcriptional level; (iv) the increased cell migration/invasion upon eIF6 over-expression was generalizable to other cell line models. Conclusions: Collectively, our data confirm and further extend the role of eIF6 in enhancing cell migration/invasion. We show that a number of membrane-associated proteins indeed vary in abundance upon eIF6 over-expression, and that the up-regulated proteins can be located within a functional network controlling cell motility and tumor metastasis. Full understanding of the role eIF6 plays in the metastatic process is important, also in view of the fact that this factor is a potentially druggable target to be exploited for new anti-cancer therapies.

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