RT Journal Article
SR Electronic
T1 Caloric restriction alters lipid metabolism to contribute to tumor growth inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.09.984302
DO 10.1101/2020.03.09.984302
A1 Evan C. Lien
A1 Anna M. Westermark
A1 Zhaoqi Li
A1 Kiera M. Sapp
A1 Matthew G. Vander Heiden
YR 2020
UL http://biorxiv.org/content/early/2020/03/10/2020.03.09.984302.abstract
AB Dietary interventions can change metabolite levels in the tumor microenvironment, which may then affect cancer cell metabolism to alter tumor growth1–6. Although caloric restriction (CR) and the ketogenic diet (KD) are often thought to inhibit tumor growth through lowering blood glucose and insulin levels7–12, only CR inhibits the growth of pancreatic ductal adenocarcinoma allografts in mice, demonstrating that this diet can limit tumor growth in other ways. A change in nutrient availability observed with CR, but not the KD, that can contribute to tumor growth inhibition is lower lipid levels in the plasma and in tumor interstitial fluid. Limiting exogenous lipid availability to cultured cancer cells results in up-regulation of stearoyl-CoA desaturase (SCD), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. Fatty acid desaturation is required to dispose of toxic saturated fatty acids, and not because monounsaturated fatty acids are specifically needed for proliferation. Surprisingly, CR also inhibits tumor SCD activity, and enforced SCD expression confers resistance to the effects of CR. Therefore, CR both limits lipid availability and impairs tumor SCD activity, thereby limiting cancer cell adaptation to a diet-induced change in the tumor microenvironment that results in tumor growth inhibition.