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

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

doi:10.1016/j.isci.2022.104518

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

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

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Article number	104518
Journal	iScience
Volume	25
Issue number	7
DOIs	https://doi.org/10.1016/j.isci.2022.104518
State	Published - Jul 15 2022
Externally published	Yes

Keywords

Cancer
Cell biology
Functional aspects of cell biology

ASJC Scopus subject areas

General

MD Anderson CCSG core facilities

Bioinformatics Shared Resource

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10.1016/j.isci.2022.104518

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title = "Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A",

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.",

keywords = "Cancer, Cell biology, Functional aspects of cell biology",

author = "Satya Narayan and Asif Raza and Iqbal Mahmud and Nayeong Koo and Garrett, {Timothy J.} and Law, {Mary E.} and Law, {Brian K.} and Sharma, {Arun K.}",

note = "Funding Information: This work was supported in part by the Department of Anatomy and Cell Biology and by Royalty Funds (# 00126956 ), University of Florida , Gainesville , FL to S.N. A.K.S thanks to the Department of Pharmacology , Penn State College of Medicine , and Penn State Cancer Institute (PSCI) for financial support. A.K.S. is also funded by NIH / NCI grant R21 CA234681 and CDMRP Lung Cancer Research Program (LCRP) Award Number W81XWH-19-1–0231. The authors thank the Organic Synthesis Shared Resource of the Penn State Cancer Institute for the synthesis of NSC49L. B.L. was supported in part by grants from the Florida Breast Cancer Foundation , the Ocala Royal Dames for Cancer Research, and the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH-15-1–0199, and NIH / NCI grant CA252400 . Publisher Copyright: {\textcopyright} 2022 The Author(s)",

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doi = "10.1016/j.isci.2022.104518",

language = "English (US)",

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T1 - Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A

AU - Narayan, Satya

AU - Raza, Asif

AU - Mahmud, Iqbal

AU - Koo, Nayeong

AU - Garrett, Timothy J.

AU - Law, Mary E.

AU - Law, Brian K.

AU - Sharma, Arun K.

N1 - Funding Information: This work was supported in part by the Department of Anatomy and Cell Biology and by Royalty Funds (# 00126956 ), University of Florida , Gainesville , FL to S.N. A.K.S thanks to the Department of Pharmacology , Penn State College of Medicine , and Penn State Cancer Institute (PSCI) for financial support. A.K.S. is also funded by NIH / NCI grant R21 CA234681 and CDMRP Lung Cancer Research Program (LCRP) Award Number W81XWH-19-1–0231. The authors thank the Organic Synthesis Shared Resource of the Penn State Cancer Institute for the synthesis of NSC49L. B.L. was supported in part by grants from the Florida Breast Cancer Foundation , the Ocala Royal Dames for Cancer Research, and the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH-15-1–0199, and NIH / NCI grant CA252400 . Publisher Copyright: © 2022 The Author(s)

PY - 2022/7/15

Y1 - 2022/7/15

N2 - 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.

AB - 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.

KW - Cancer

KW - Cell biology

KW - Functional aspects of cell biology

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DO - 10.1016/j.isci.2022.104518

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AN - SCOPUS:85132242489

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

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M1 - 104518

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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