Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached
AuthorsWilcock, D. J.
Badrock, A. P.
Wong, C. W.
Southam, A. D.
Telfer, B. A.
Lloyd, G. R.
Dunn, W. B.
Lorigan, Paul C
Smith, M. P.
Hurlstone, A. F. L.
AffiliationDivision of Cancer Studies, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK
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AbstractDysregulated 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.
CitationWilcock DJ, Badrock AP, Wong CW, Owen R, Guerin M, Southam AD, et al. Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached. Vol. 39, Cell Reports. Elsevier BV; 2022. p. 110995.
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