Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling.
Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small m...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3257223?pdf=render |
| _version_ | 1818971562520346624 |
|---|---|
| author | Simon R Stockwell Georgina Platt S Elaine Barrie Georgia Zoumpoulidou Robert H Te Poele G Wynne Aherne Stuart C Wilson Peter Sheldrake Edward McDonald Mathilde Venet Christelle Soudy Frédéric Elustondo Laurent Rigoreau Julian Blagg Paul Workman Michelle D Garrett Sibylle Mittnacht |
| author_facet | Simon R Stockwell Georgina Platt S Elaine Barrie Georgia Zoumpoulidou Robert H Te Poele G Wynne Aherne Stuart C Wilson Peter Sheldrake Edward McDonald Mathilde Venet Christelle Soudy Frédéric Elustondo Laurent Rigoreau Julian Blagg Paul Workman Michelle D Garrett Sibylle Mittnacht |
| author_sort | Simon R Stockwell |
| collection | DOAJ |
| description | Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for pathway selective agent development. We demonstrate that consistent with its mode of action CCT020312 is capable of delivering potent, and EIF2AK3 selective, proliferation control and can act as a sensitizer to chemotherapy-associated stresses as elicited by taxanes. |
| first_indexed | 2024-12-20T14:54:21Z |
| format | Article |
| id | doaj.art-921c0f22c6cd45cb99c4eb1f472162a4 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T14:54:21Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-921c0f22c6cd45cb99c4eb1f472162a42022-12-21T19:36:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0171e2856810.1371/journal.pone.0028568Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling.Simon R StockwellGeorgina PlattS Elaine BarrieGeorgia ZoumpoulidouRobert H Te PoeleG Wynne AherneStuart C WilsonPeter SheldrakeEdward McDonaldMathilde VenetChristelle SoudyFrédéric ElustondoLaurent RigoreauJulian BlaggPaul WorkmanMichelle D GarrettSibylle MittnachtHuman cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for pathway selective agent development. We demonstrate that consistent with its mode of action CCT020312 is capable of delivering potent, and EIF2AK3 selective, proliferation control and can act as a sensitizer to chemotherapy-associated stresses as elicited by taxanes.http://europepmc.org/articles/PMC3257223?pdf=render |
| spellingShingle | Simon R Stockwell Georgina Platt S Elaine Barrie Georgia Zoumpoulidou Robert H Te Poele G Wynne Aherne Stuart C Wilson Peter Sheldrake Edward McDonald Mathilde Venet Christelle Soudy Frédéric Elustondo Laurent Rigoreau Julian Blagg Paul Workman Michelle D Garrett Sibylle Mittnacht Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. PLoS ONE |
| title | Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. |
| title_full | Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. |
| title_fullStr | Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. |
| title_full_unstemmed | Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. |
| title_short | Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. |
| title_sort | mechanism based screen for g1 s checkpoint activators identifies a selective activator of eif2ak3 perk signalling |
| url | http://europepmc.org/articles/PMC3257223?pdf=render |
| work_keys_str_mv | AT simonrstockwell mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT georginaplatt mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT selainebarrie mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT georgiazoumpoulidou mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT roberthtepoele mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT gwynneaherne mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT stuartcwilson mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT petersheldrake mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT edwardmcdonald mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT mathildevenet mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT christellesoudy mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT fredericelustondo mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT laurentrigoreau mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT julianblagg mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT paulworkman mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT michelledgarrett mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling AT sibyllemittnacht mechanismbasedscreenforg1scheckpointactivatorsidentifiesaselectiveactivatorofeif2ak3perksignalling |