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通过调控涉及蛋白磷酸酶2A的新途径使耐FOLFOX的结肠癌细胞致敏

Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A.

作者信息

Narayan Satya, Raza Asif, Mahmud Iqbal, Koo Nayeong, Garrett Timothy J, Law Mary E, Law Brian K, Sharma Arun K

机构信息

Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610, USA.

Department of Pharmacology, Penn State University College of Medicine, Penn State Cancer Institute, Hershey, PA 17033, USA.

出版信息

iScience. 2022 Jun 3;25(7):104518. doi: 10.1016/j.isci.2022.104518. eCollection 2022 Jul 15.

DOI:10.1016/j.isci.2022.104518
PMID:35754740
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9218363/
Abstract

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.

摘要

用FOLFOX治疗结直肠癌（CRC）显示出一定疗效，但这些肿瘤会很快对这种治疗产生耐药性。我们观察到在对FOLFOX耐药的CRC细胞中，AKT1/mTOR/4EBP1的磷酸化增加以及p21水平升高。我们鉴定出一种小分子NSC49L，它能刺激蛋白磷酸酶2A（PP2A）的活性，下调AKT1/mTOR/4EBP1轴，并抑制p21的翻译。我们已提供证据表明，在p21基因敲低的CRC细胞中，NSC49L和TRAIL介导的致敏作用协同诱导，而在p21过表达的细胞中则相反。p21与procaspase 3结合并阻止caspase 3的激活。我们已表明，TRAIL通过NSC49L介导的p21翻译下调激活caspase 3，从而将procaspase 3切割成caspase 3来诱导细胞凋亡。NSC49L不影响整体蛋白质合成。这些研究提供了对NSC49L作为PP2A激动剂的机制理解，以及它与TRAIL联合使用如何使对FOLFOX耐药的CRC细胞致敏。

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本文引用的文献

1
Cancer statistics, 2022.癌症统计数据，2022 年。
CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan 12.
2
TRAIL of Hope Meeting Resistance in Cancer.希望之路在癌症治疗中遭遇阻力。
Trends Cancer. 2020 Dec;6(12):989-1001. doi: 10.1016/j.trecan.2020.06.006. Epub 2020 Jul 24.
3
Retracted: Allosteric Activators of Protein Phosphatase 2A Display Broad Antitumor Activity Mediated by Dephosphorylation of MYBL2.撤回：蛋白磷酸酶 2A 的别构激活剂通过去磷酸化 MYBL2 显示出广泛的抗肿瘤活性。
结肠癌中治疗耐药性循环肿瘤细胞的表观基因组重编程
Front Cell Dev Biol. 2023 Dec 21;11:1291179. doi: 10.3389/fcell.2023.1291179. eCollection 2023.
4
Altering phosphorylation in cancer through PP2A modifiers.通过PP2A修饰剂改变癌症中的磷酸化作用。
Cancer Cell Int. 2024 Jan 6;24(1):11. doi: 10.1186/s12935-023-03193-1.
Cell. 2020 Apr 30;181(3):702-715.e20. doi: 10.1016/j.cell.2020.03.051. Epub 2020 Apr 20.
4
Selective PP2A Enhancement through Biased Heterotrimer Stabilization.通过偏向异三聚体稳定化选择性增强 PP2A。
Cell. 2020 Apr 30;181(3):688-701.e16. doi: 10.1016/j.cell.2020.03.038. Epub 2020 Apr 20.
5
Targeting apoptosis in cancer therapy.靶向细胞凋亡治疗癌症。
Nat Rev Clin Oncol. 2020 Jul;17(7):395-417. doi: 10.1038/s41571-020-0341-y. Epub 2020 Mar 23.
6
Disulfide bond-disrupting agents activate the tumor necrosis family-related apoptosis-inducing ligand/death receptor 5 pathway.二硫键破坏剂激活肿瘤坏死因子家族相关凋亡诱导配体/死亡受体5通路。
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7
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8
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9
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Cancer Gene Ther. 2020 Jun;27(6):448-460. doi: 10.1038/s41417-019-0117-7. Epub 2019 Jul 1.
10
The NMR-based characterization of the FTY720-SET complex reveals an alternative mechanism for the attenuation of the inhibitory SET-PP2A interaction.基于 NMR 的 FTY720-SET 复合物的表征揭示了抑制 SET-PP2A 相互作用衰减的替代机制。
FASEB J. 2019 Jun;33(6):7647-7666. doi: 10.1096/fj.201802264R. Epub 2019 Mar 27.