Abstract
Despite the importance of mitochondrial fatty acid oxidation (FAO) in cancer metabolism, the biological mechanisms responsible for the FAO in cancer and therapeutic intervention based on catabolic metabolism are not well defined. In this study, we observe that Snail (SNAI1), a key transcriptional repressor of epithelial-mesenchymal transition, enhances catabolic FAO, allowing pro-survival of breast cancer cells in a starved environment. Mechanistically, Snail suppresses mitochondrial ACC2 (ACACB) by binding to a series of E-boxes located in its proximal promoter, resulting in decreased malonyl-CoA level. Malonyl-CoA being a well-known endogenous inhibitor of fatty acid transporter carnitine palmitoyltransferase 1 (CPT1), the suppression of ACC2 by Snail activates CPT1-dependent FAO, generating ATP and decreasing NADPH consumption. Importantly, combinatorial pharmacologic inhibition of pentose phosphate pathway and FAO with clinically available drugs efficiently reverts Snail-mediated metabolic reprogramming and suppresses in vivo metastatic progression of breast cancer cells. Our observations provide not only a mechanistic link between epithelial-mesenchymal transition and catabolic rewiring but also a novel catabolism-based therapeutic approach for inhibition of cancer progression.
Highlights
During the natural history of human solid cancer, cancer cells repeatedly encounter a metabolic-starved microenvironment which has to be overcome for successful cancer progression (Aktipis et al, 2013)
adenosine 59-triphosphate (ATP) can originate from many sources in the metabolic circuit, mitochondrial fatty acid oxidation (FAO) is the most efficient process for generating ATP, especially in glucose-starved condition, and carnitine palmitoyltransferase 1 (CPT1) is the gatekeeper of the FAO
To obtain direct evidence that the ATP is generated from fatty acid rather than glucose, we administered palmitate–BSA conjugate as a mitochondrial FAO substrate to breast cancer cells in a glucose-starved environment
Summary
During the natural history of human solid cancer, cancer cells repeatedly encounter a metabolic-starved microenvironment which has to be overcome for successful cancer progression (Aktipis et al, 2013). ATP levels in the clinical samples were well maintained in the glucose-starved tumor microenvironment (Walenta et al, 2003; Hirayama et al, 2009), suggesting that essential ATP may be generated from something other than glucose. Matrix-detached cancer cells encounter ATP deficiency and oxidative stress due to loss of glucose transport (Schafer et al, 2009). In these starved conditions, ATP, mainly from oxidative phosphorylation, as well as NADPH for reductive biosynthesis, are essential metabolites required for overcoming metabolic stress and for successful cancer progression, catabolic reprogramming by oncogenic signaling is not fully understood
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