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 a Show more
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 NSC49Lmediated 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. Show less