p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells DOI Creative Commons
Amy Tarangelo, Leslie Magtanong,

Kathryn Bieging-Rolett

et al.

Cell Reports, Journal Year: 2018, Volume and Issue: 22(3), P. 569 - 575

Published: Jan. 1, 2018

How cancer cells respond to nutrient deprivation remains poorly understood. In certain cells, of cystine induces a non-apoptotic, iron-dependent form cell death termed ferroptosis. Recent evidence suggests that ferroptosis sensitivity may be modulated by the stress-responsive transcription factor and canonical tumor suppressor protein p53. Using CRISPR/Cas9 genome editing, small-molecule probes, high-resolution, time-lapse imaging, we find stabilization wild-type p53 delays onset in response deprivation. This delay requires transcriptional target CDKN1A (encoding p21) is associated with both slower depletion intracellular glutathione reduced accumulation toxic lipid-reactive oxygen species (ROS). Thus, p53-p21 axis help cope metabolic stress induced delaying non-apoptotic death.

Language: Английский

Tissue of origin dictates branched-chain amino acid metabolism in mutantKras-driven cancers DOI Open Access
Jared R. Mayers, Margaret E. Torrence, Laura V. Danai

et al.

Science, Journal Year: 2016, Volume and Issue: 353(6304), P. 1161 - 1165

Published: Sept. 8, 2016

Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on pathways is unknown. Kras activation Trp53 deletion in the pancreas or lung result pancreatic ductal adenocarinoma (PDAC) non–small carcinoma (NSCLC), respectively, but despite same initiating events, these tumors use branched-chain amino acids (BCAAs) differently. NSCLC incorporate free BCAAs into protein as a nitrogen source, whereas PDAC decreased BCAA uptake. These differences are reflected expression levels of catabolic enzymes both mice humans. Loss Bcat1 Bcat2, responsible use, impairs tumor formation, not required arguing origin an important determinant how cancers satisfy their requirements.

Language: Английский

Citations

498
The Hallmarks of Ferroptosis DOI Open Access
Scott J. Dixon, Brent R. Stockwell

Annual Review of Cancer Biology, Journal Year: 2018, Volume and Issue: 3(1), P. 35 - 54

Published: Oct. 25, 2018

Ferroptosis is a nonapoptotic, iron-dependent form of cell death that can be activated in cancer cells by natural stimuli and synthetic agents. Three essential hallmarks define ferroptosis, namely: the loss lipid peroxide repair capacity phospholipid hydroperoxidase GPX4, availability redox-active iron, oxidation polyunsaturated fatty acid (PUFA)-containing phospholipids. Several processes including RAS/MAPK signaling, amino iron metabolism, ferritinophagy, epithelial-to-mesenchymal transition, adhesion, mevalonate biosynthesis modulate susceptibility to ferroptosis. sensitivity also governed p53 KEAP1/NRF2 activity, linking ferroptosis function key tumor suppressor pathways. Together these findings highlight role as an emerging concept biology attractive target for precision medicine discovery.

Language: Английский

Citations

498
The Two Faces of Reactive Oxygen Species in Cancer DOI Open Access
Colleen R. Reczek, Navdeep S. Chandel

Annual Review of Cancer Biology, Journal Year: 2016, Volume and Issue: 1(1), P. 79 - 98

Published: Aug. 27, 2016

Reactive oxygen species (ROS), now appreciated for their cellular signaling capabilities, have a dual role in cancer. On the one hand, ROS can promote protumorigenic signaling, facilitating cancer cell proliferation, survival, and adaptation to hypoxia. other antitumorigenic trigger oxidative stress-induced death. To hyperactivate pathways necessary transformation tumorigenesis, cells increase rate of production compared with normal cells. Concomitantly, order maintain homeostasis evade death, antioxidant capacity. Compared cells, this altered redox environment may susceptibility ROS-manipulation therapies. In review, we discuss two faces cancer, potential mechanisms underlying opposing therapeutic approaches targeting ROS.

Language: Английский

Citations

497
ROS in Cancer: The Burning Question DOI
Iok In Christine Chio, David A. Tuveson

Trends in Molecular Medicine, Journal Year: 2017, Volume and Issue: 23(5), P. 411 - 429

Published: April 18, 2017

Language: Английский

Citations

478
p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells DOI Creative Commons
Amy Tarangelo, Leslie Magtanong,

Kathryn Bieging-Rolett

et al.

Cell Reports, Journal Year: 2018, Volume and Issue: 22(3), P. 569 - 575

Published: Jan. 1, 2018

How cancer cells respond to nutrient deprivation remains poorly understood. In certain cells, of cystine induces a non-apoptotic, iron-dependent form cell death termed ferroptosis. Recent evidence suggests that ferroptosis sensitivity may be modulated by the stress-responsive transcription factor and canonical tumor suppressor protein p53. Using CRISPR/Cas9 genome editing, small-molecule probes, high-resolution, time-lapse imaging, we find stabilization wild-type p53 delays onset in response deprivation. This delay requires transcriptional target CDKN1A (encoding p21) is associated with both slower depletion intracellular glutathione reduced accumulation toxic lipid-reactive oxygen species (ROS). Thus, p53-p21 axis help cope metabolic stress induced delaying non-apoptotic death.

Language: Английский

Citations

469