PUBLICATION
Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached
- Authors
- Wilcock, D.J., Badrock, A.P., Wong, C.W., Owen, R., Guerin, M., Southam, A.D., Johnston, H., Telfer, B.A., Fullwood, P., Watson, J., Ferguson, H., Ferguson, J., Lloyd, G.R., Jankevics, A., Dunn, W.B., Wellbrock, C., Lorigan, P., Ceol, C., Francavilla, C., Smith, M.P., Hurlstone, A.F.L.
- ID
- ZDB-PUB-220623-7
- Date
- 2022
- Source
- Cell Reports 39: 110995 (Journal)
- Registered Authors
- Ceol, Craig, Hurlstone, Adam
- Keywords
- CP: Cancer, DGAT1, SOD1, fatty acids, lipid droplets, melanoma, oxidative stress, reactive oxygen species
- MeSH Terms
-
- Animals
- Diacylglycerol O-Acyltransferase*/genetics
- Diacylglycerol O-Acyltransferase*/metabolism
- Melanoma*
- Oncogene Proteins/metabolism
- Oxidative Stress
- Reactive Oxygen Species
- Triglycerides
- Zebrafish/metabolism
- PubMed
- 35732120 Full text @ Cell Rep.
Citation
Wilcock, D.J., Badrock, A.P., Wong, C.W., Owen, R., Guerin, M., Southam, A.D., Johnston, H., Telfer, B.A., Fullwood, P., Watson, J., Ferguson, H., Ferguson, J., Lloyd, G.R., Jankevics, A., Dunn, W.B., Wellbrock, C., Lorigan, P., Ceol, C., Francavilla, C., Smith, M.P., Hurlstone, A.F.L. (2022) Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached. Cell Reports. 39:110995.
Abstract
Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cancer cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. Excess FAs are toxic to non-transformed cells but surprisingly not to cancer cells. Molecules underlying this cancer adaptation may provide alternative drug targets. Here, we demonstrate that diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, is frequently up-regulated in melanoma, allowing melanoma cells to tolerate excess FA. DGAT1 over-expression alone transforms p53-mutant zebrafish melanocytes and co-operates with oncogenic BRAF or NRAS for more rapid melanoma formation. Antagonism of DGAT1 induces oxidative stress in melanoma cells, which adapt by up-regulating cellular reactive oxygen species defenses. We show that inhibiting both DGAT1 and superoxide dismutase 1 profoundly suppress tumor growth through eliciting intolerable oxidative stress.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping