Deregulation of the Phosphoinositide 3-kinase (PI3K) pathway is associated with metabolic flexibility leading to cancer poor prognosis. Here, the authors show that targeting both glutamine degradation Show more
Deregulation of the Phosphoinositide 3-kinase (PI3K) pathway is associated with metabolic flexibility leading to cancer poor prognosis. Here, the authors show that targeting both glutamine degradation and mTOR inhibition effectively kills PI3K-altered cancer cells in pre-clinical and clinical settings for T-cell acute lymphoblastic leukemia and solid cancer. Show less
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription.
Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well
known. In Show more
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription.
Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well
known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29,
SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 µM. The
inhibitory concentrations of cell growth by 50% (IC50 ) of oxaliplatin were 4.40–12.7-fold significantly
higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt
and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in
phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly,
an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further
inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate
cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of
Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK
may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to
anticancer drugs.
Human Colorectal Cancer.
Biomedicines 2022, 10, 2690. Show less
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