Matches in SemOpenAlex for { <https://semopenalex.org/work/W2809954788> ?p ?o ?g. }
Showing items 1 to 77 of
77
with 100 items per page.
- W2809954788 abstract "Introduction c-Myc plays a central role in cellular proliferation, differentiation, and apoptosis. Therefore its deregulation represents a powerful trigger of tumorigenesis, particularly in colorectal cancer (CRC). It has been shown that the MEK/ERK pathway phosphorylates c-Myc on serine 62, which stabilises c-Myc by preventing ubiquitin/proteasomal degradation. We recently reported that MEK/ERK inhibition is counteracted by over-activation of p38α MAPK. Here, we identified cellular mechanisms that lead to c-Myc deregulation, which is a crucial issue for improving CRC treatment and survival. Material and methods The cross-talk between p38α and ERK was assessed in CRC cell lines and in APC Min/+ mice, a murine model of familial adenomatous polyposis. To this aim, animals were treated with the p38α inhibitor 4-(4-Fluorophenyl)−2-(4-hydroxyphenyl)−5-(4-pyridyl)−1H-imidazole (SB202190) alone or in combination with the MEK1 inhibitor N-[(2R)−2,3-Dihydroxypropoxy]−3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (PD0325901). In order to evaluate the role of p38α and ERK in c-Myc regulation, we used pharmacological inhibitors of these two kinases alone or in combination with inhibitors of the transcriptional mechanism, translational process and proteasome in CRC cell lines. Moreover, the function of p38α and ERK in Myc stabilisation was assessed by genetic ablation. Results and discussions Here we show that concomitant inhibition of the p38α and MEK/ERK pathways significantly increases the survival of APC Min/+ mice in which tumorigenesis is driven by c-Myc deregulation. Genetic ablation of p38α and ERK revealed that these two MAPKs do not regulate c-Myc expression, nor do they affect c-Myc protein translational process. We found that p38α and ERK collaborate in c-Myc stabilisation by inhibiting its proteasomal degradation in CRC cell lines. These results were also confirmed by using the p38α and ERK pharmacological inhibitors LY2228820 (Ralimetinib) and GSK1120212 (Mekinist), respectively, which are currently in clinical trials for inflammatory diseases and cancer. Conclusion Since c-MYC supports the processes required for normal growth and homeostasis, its ablation is less attractive than modulation of its expression or function. Our results confirmed the essential role of the MAPK/c-Myc axis in intestinal tumorigenesis regulation, suggesting MAPK manipulation as a potential therapeutic approach to counteract c-Myc dependent carcinogenesis." @default.
- W2809954788 created "2018-07-10" @default.
- W2809954788 creator A5017266289 @default.
- W2809954788 creator A5033117700 @default.
- W2809954788 creator A5048973625 @default.
- W2809954788 creator A5050382030 @default.
- W2809954788 creator A5053318866 @default.
- W2809954788 creator A5058191614 @default.
- W2809954788 creator A5085560873 @default.
- W2809954788 creator A5087975070 @default.
- W2809954788 date "2018-06-01" @default.
- W2809954788 modified "2023-09-23" @default.
- W2809954788 title "PO-006 The MAPK/c-Myc axis in CRC: new pathogenic mechanisms and therapeutic approaches" @default.
- W2809954788 doi "https://doi.org/10.1136/esmoopen-2018-eacr25.51" @default.
- W2809954788 hasPublicationYear "2018" @default.
- W2809954788 type Work @default.
- W2809954788 sameAs 2809954788 @default.
- W2809954788 citedByCount "0" @default.
- W2809954788 crossrefType "journal-article" @default.
- W2809954788 hasAuthorship W2809954788A5017266289 @default.
- W2809954788 hasAuthorship W2809954788A5033117700 @default.
- W2809954788 hasAuthorship W2809954788A5048973625 @default.
- W2809954788 hasAuthorship W2809954788A5050382030 @default.
- W2809954788 hasAuthorship W2809954788A5053318866 @default.
- W2809954788 hasAuthorship W2809954788A5058191614 @default.
- W2809954788 hasAuthorship W2809954788A5085560873 @default.
- W2809954788 hasAuthorship W2809954788A5087975070 @default.
- W2809954788 hasBestOaLocation W28099547881 @default.
- W2809954788 hasConcept C121608353 @default.
- W2809954788 hasConcept C184235292 @default.
- W2809954788 hasConcept C185592680 @default.
- W2809954788 hasConcept C502942594 @default.
- W2809954788 hasConcept C51551487 @default.
- W2809954788 hasConcept C54355233 @default.
- W2809954788 hasConcept C555283112 @default.
- W2809954788 hasConcept C57074206 @default.
- W2809954788 hasConcept C86803240 @default.
- W2809954788 hasConcept C95444343 @default.
- W2809954788 hasConceptScore W2809954788C121608353 @default.
- W2809954788 hasConceptScore W2809954788C184235292 @default.
- W2809954788 hasConceptScore W2809954788C185592680 @default.
- W2809954788 hasConceptScore W2809954788C502942594 @default.
- W2809954788 hasConceptScore W2809954788C51551487 @default.
- W2809954788 hasConceptScore W2809954788C54355233 @default.
- W2809954788 hasConceptScore W2809954788C555283112 @default.
- W2809954788 hasConceptScore W2809954788C57074206 @default.
- W2809954788 hasConceptScore W2809954788C86803240 @default.
- W2809954788 hasConceptScore W2809954788C95444343 @default.
- W2809954788 hasLocation W28099547881 @default.
- W2809954788 hasLocation W28099547882 @default.
- W2809954788 hasLocation W28099547883 @default.
- W2809954788 hasOpenAccess W2809954788 @default.
- W2809954788 hasPrimaryLocation W28099547881 @default.
- W2809954788 hasRelatedWork W1458142890 @default.
- W2809954788 hasRelatedWork W1985144105 @default.
- W2809954788 hasRelatedWork W1990298698 @default.
- W2809954788 hasRelatedWork W1991395730 @default.
- W2809954788 hasRelatedWork W2003463518 @default.
- W2809954788 hasRelatedWork W2057507337 @default.
- W2809954788 hasRelatedWork W2074714811 @default.
- W2809954788 hasRelatedWork W2075371342 @default.
- W2809954788 hasRelatedWork W2094810771 @default.
- W2809954788 hasRelatedWork W2144169031 @default.
- W2809954788 hasRelatedWork W2211890826 @default.
- W2809954788 hasRelatedWork W2761912328 @default.
- W2809954788 hasRelatedWork W2786746973 @default.
- W2809954788 hasRelatedWork W2899353968 @default.
- W2809954788 hasRelatedWork W2902133547 @default.
- W2809954788 hasRelatedWork W2944267355 @default.
- W2809954788 hasRelatedWork W3123663572 @default.
- W2809954788 hasRelatedWork W3130896959 @default.
- W2809954788 hasRelatedWork W2181439810 @default.
- W2809954788 hasRelatedWork W2905153470 @default.
- W2809954788 isParatext "false" @default.
- W2809954788 isRetracted "false" @default.
- W2809954788 magId "2809954788" @default.
- W2809954788 workType "article" @default.