Editors' ChoiceCancer Metabolism

A cancerous connection for creatine

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Science Signaling  30 Mar 2021:
Vol. 14, Issue 676, eabi7099
DOI: 10.1126/scisignal.abi7099

Obesity induces adipocytes to release creatine that is used by nearby breast cancer cells to fuel growth.

Obesity in breast cancer patients correlates with an increased risk of disease recurrence and aggressiveness and death. Maguire et al. found that in the obese state, adipocytes supplied nearby breast cancer cells with creatine, which is a reservoir for high-energy phosphates when phosphorylated (see also Reitman). In a triple-negative orthotopic breast cancer model using E0771 cells, mice on a high-fat diet had more hypoxic, larger tumors than those on a normal chow or low-fat diet. Compared to adipose tissue from the contralateral mammary fat pad in obese mice, peritumoral adipose tissue had increased expression of the gene encoding glycine amidinotransferase (Gatm), the rate-limiting enzyme in creatine biosynthesis. Furthermore, tumors in obese mice had increased concentrations of creatine. Exogenously supplied creatine in the diet did not affect tumor progression, suggesting that the breast cancer cells obtained creatine from the tumor microenvironment. When rendered obese by a high-fat diet and orthotopically implanted with breast tumors, mice with an adipocyte-specific deletion of Gatm survived longer than did control mice. RNAi-mediated knockdown of the creatine carrier SLC6A8 in E0771 cells suppressed creatine uptake in vitro and tumor growth in vivo. E0771 cells in obese mice showed increased expression of not only Slc6a8, but also Acsbg1, which encodes an enzyme that catalyzes the conversion of long-chain fatty acids to long-chain fatty acyl-CoAs. Overexpression of ACSBG1 in E0771 cells increased tumor progression in obese mice in an SLC6A8-dependent manner, and these cells had increased ATP and phosphocreatine content. In contrast, combining RNAi-mediated knockdown of Acsbg1 with a pharmacological inhibitor of acyl-CoA synthetase activity prevented the increase in tumor volume in obese mice. SLC6A8 and ACSBG1 expression in human breast cancer samples correlated with poor prognosis independently of obesity status. Thus, obesity induces adipocytes to secrete creatine into the tumor microenvironment, thereby fueling the growth of nearby breast cancer cells.

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