Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached.



Wilcock, Daniel J, Badrock, Andrew P, Wong, Chun W, Owen, Rhys ORCID: 0000-0001-8024-087X, Guerin, Melissa, Southam, Andrew D, Johnston, Hannah, Telfer, Brian A, Fullwood, Paul, Watson, Joanne ORCID: 0000-0002-7754-276X
et al (show 11 more authors) (2022) Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached. Cell reports, 39 (12). 110995-.

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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.

Item Type: Article
Uncontrolled Keywords: Animals, Zebrafish, Melanoma, Reactive Oxygen Species, Triglycerides, Oncogene Proteins, Oxidative Stress, Diacylglycerol O-Acyltransferase
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 17 Oct 2022 14:37
Last Modified: 14 Mar 2024 18:58
DOI: 10.1016/j.celrep.2022.110995
Open Access URL: https://doi.org/10.1016/j.celrep.2022.110995
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3165551