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
Efforts to identify anti-cancer therapeutics and understand tumor-immune interactions are built with in vitro models that do not match the microenvironmental characteristics of human tissues. Using in Show more
Efforts to identify anti-cancer therapeutics and understand tumor-immune interactions are built with in vitro models that do not match the microenvironmental characteristics of human tissues. Using in vitro models which mimic the physical properties of healthy or cancerous tissues and a physiologically relevant culture medium, we demonstrate that the chemical and physical properties of the microenvironment regulate the composition and topology of the glycocalyx. Remarkably, we find that cancer and age-related Show less
The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stres Show more
The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during Show less