文章基本信息

标题：Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A
本地全文：下载
作者：Satya Narayan ; Asif Raza ; Iqbal Mahmud 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：7
页码：1-29
DOI：10.1016/j.isci.2022.104518
语种：English
出版社：Elsevier
摘要：SummaryThe 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.Graphical abstractDisplay OmittedHighlights•A PP2A agonist has been identified that sensitizes FOLFOX-resistant CRC cells•It downregulates AKT1/mTOR/4EBP1 axis and p21 translation•Describes a link between p21 and procaspase 3 in TRAIL-resistance•Downregulation of p21 synergistically induces TRAIL-mediated apoptosisCell biology; Functional aspects of cell biology; Cancer