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

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

Authors

Satya Narayan¹, Asif Raza², Iqbal Mahmud³, Nayeong Koo¹, Timothy J Garrett³, Mary E Law⁴, Brian K Law⁴, Arun K Sharma²

Affiliations

¹ Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL 32610, USA.
² Department of Pharmacology, Penn State University College of Medicine, Penn State Cancer Institute, Hershey, PA 17033, USA.
³ Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
⁴ Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.

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.

Abstract

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