Upregulation of Smad7, an inhibitor of transforming growth factor-β1 (TGF-β1), occurs in sporadic colorectal cancer (CRC) and knockdown of Smad7 inhibits CRC cell growth, a phenomenon that associates with decreased expression of cell division cycle 25 homolog A and arrest of cells in the S phase of the cell cycle. These findings occur in CRC cells unresponsive to TGF-β1, thus suggesting the existence of a Smad7-mediated TGF-β1-independent mechanism that controls CRC cell behavior. Here we show that Smad7 inhibition with a specific Smad7 antisense oligonucleotide upregulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, a transcription factor involved in the regulation of cell cycle arrest and induction of cell death, and induces activating transcription factor 4 (ATF4) and CCAAT/enhancer binding protein homology protein (CHOP), two downstream targets of eIF2α. Among the upstream kinases that control eIF2α phosphorylation, the serine-threonine protein kinase RNA (PKR), but not general control non-derepressible 2 (GCN2) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), is activated by Smad7 knockdown. PKR silencing abolishes Smad7 antisense-induced eIF2α phosphorylation and ATF4/CHOP induction, thereby preventing Smad7 antisense-driven cell death. Smad7 inhibition diminishes interaction of PKR with protein kinase inhibitor p58 (p58IPK), a cellular inhibitor of PKR, but does not change the expression and/or activity of other factors involved in the control of PKR activation. These findings delineate a novel mechanism by which Smad7 knockdown promotes CRC cell death.

De Simone, V., Bevivino, G., Sedda, S., Izzo, R., Laudisi, F., Dinallo, V., et al. (2017). Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death. CELL DEATH & DISEASE, 8(3), e2681-e2681 [10.1038/cddis.2017.103].

Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death

De Simone, Veronica;Bevivino, Gerolamo;Izzo, Roberta;Dinallo, Vincenzo;Colantoni, Alfredo;Ortenzi, Angela;Rossi, Piero;Sica, Giuseppe S.;Fantini, Massimo C.;Stolfi, Carmine;Monteleone, Giovanni
2017-01-01

Abstract

Upregulation of Smad7, an inhibitor of transforming growth factor-β1 (TGF-β1), occurs in sporadic colorectal cancer (CRC) and knockdown of Smad7 inhibits CRC cell growth, a phenomenon that associates with decreased expression of cell division cycle 25 homolog A and arrest of cells in the S phase of the cell cycle. These findings occur in CRC cells unresponsive to TGF-β1, thus suggesting the existence of a Smad7-mediated TGF-β1-independent mechanism that controls CRC cell behavior. Here we show that Smad7 inhibition with a specific Smad7 antisense oligonucleotide upregulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, a transcription factor involved in the regulation of cell cycle arrest and induction of cell death, and induces activating transcription factor 4 (ATF4) and CCAAT/enhancer binding protein homology protein (CHOP), two downstream targets of eIF2α. Among the upstream kinases that control eIF2α phosphorylation, the serine-threonine protein kinase RNA (PKR), but not general control non-derepressible 2 (GCN2) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), is activated by Smad7 knockdown. PKR silencing abolishes Smad7 antisense-induced eIF2α phosphorylation and ATF4/CHOP induction, thereby preventing Smad7 antisense-driven cell death. Smad7 inhibition diminishes interaction of PKR with protein kinase inhibitor p58 (p58IPK), a cellular inhibitor of PKR, but does not change the expression and/or activity of other factors involved in the control of PKR activation. These findings delineate a novel mechanism by which Smad7 knockdown promotes CRC cell death.
2017
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/12 - GASTROENTEROLOGIA
English
Con Impact Factor ISI
Activating Transcription Factor 4; Cell Cycle Checkpoints; Cell Death; Colonic Neoplasms; Endoplasmic Reticulum; Eukaryotic Initiation Factor-2; HCT116 Cells; HSP40 Heat-Shock Proteins; Humans; Phosphorylation; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Signal Transduction; Smad7 Protein; Transcription Factor CHOP; Transforming Growth Factor beta1; Up-Regulation; eIF-2 Kinase; Immunology; Cellular and Molecular Neuroscience; Cell Biology; Cancer Research
http://www.nature.com/cddis/marketing/index.html
De Simone, V., Bevivino, G., Sedda, S., Izzo, R., Laudisi, F., Dinallo, V., et al. (2017). Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death. CELL DEATH & DISEASE, 8(3), e2681-e2681 [10.1038/cddis.2017.103].
De Simone, V; Bevivino, G; Sedda, S; Izzo, R; Laudisi, F; Dinallo, V; Franzã, E; Colantoni, A; Ortenzi, A; Salvatori, S; Rossi, P; Sica, Gs; Fantini,...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/192175
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