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Chemoproteomic Mapping of Glycolytic Targetome in Cancer Cells

ABSTRACT: Hyperactivated glycolysis is a metabolic hallmark of most cancer cells. Although sporadic information has revealed that glycolytic metabolites possess non-metabolic functions as signaling molecules, it remains largely elusive how these metabolites interact with and functionally regulate their binding targets. Here we introduce a Target Responsive Accessibility Profiling (TRAP) approach that measures ligand binding-induced accessibility changes for target identification through globally labeling reactive proteinaceous lysines. With TRAP, we mapped 913 responsive target candidates and 2,487 interactions for 10 major glycolytic metabolites in a model cancer cell line. The wide targetome depicted by TRAP unveils diverse regulatory modalities of glycolytic metabolites involving direct perturbation of carbohydrate metabolism enzymes, intervention of an orphan transcriptional protein’s activity, and modulation of targetome-level acetylation. These results deepen our understanding of how glycolysis orchestrates signaling pathways in cancer cells in support of their survival and inspire future exploitation of the glycolytic targetome for cancer therapy development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225738 | GEO | 2023/04/12

REPOSITORIES: GEO

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Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics. Since MCT1 levels are elevated in glycolytic and malignant breast tumors, we hypothesized that MCT1 may contribute to the Warburg effect metabolic phenotype. To test this hypothesis, we generated whole genome microarray data from breast cancer cell lines either a) expressing a short hairpin (sh)RNA-mediated stable knockdown of MCT1; or b) treated for 24 hours with an MCT1 inhibitor (AZD3965). Scramble shRNA or DMSO were used as controls, and all conditions were analzed in triplicate. The cell lines used â HS578T, SUM149PT, and SUM159PT â are among the most glycolytic in a panel of 31 breast cancer cell lines.

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Chemoproteomic Mapping of Glycolytic Targetome in Cancer Cells

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