Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A.
Cancer
Cell biology
Functional aspects of cell biology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
15 Jul 2022
15 Jul 2022
Historique:
received:
16
08
2021
revised:
16
05
2022
accepted:
30
05
2022
entrez:
27
6
2022
pubmed:
28
6
2022
medline:
28
6
2022
Statut:
epublish
Résumé
The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells.
Identifiants
pubmed: 35754740
doi: 10.1016/j.isci.2022.104518
pii: S2589-0042(22)00789-1
pmc: PMC9218363
doi:
Types de publication
Journal Article
Langues
eng
Pagination
104518Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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