Abstract 2381: Interleukin-4 receptor signaling induces glycolysis in triple negative breast cancer

Abstract

In the context of cancer biology Th2 cytokines such as IL4 and IL13 are most studied for their effects on immune cells such as macrophages. IL-4 receptor is established to cause polarization of macrophages to a pro-tumor M2 phenotype. While much is known about the signaling effects of IL-4 in immune cells there is relatively little known about its effects in cancer cells that express the receptor. Our lab has established a role of signaling in IL4 receptor expressing cancer cells for promoting metastasis. Many of the effects of IL-4 signaling in immune cells are accompanied by metabolic changes. Thus, we aimed to study the effects of IL-4 signaling on metabolism in breast cancer to better understand how these metabolic changes might induce metastatic phenotypes associated with IL-4 stimulation. IL-4 increased glucose uptake in multiple human TNBC cell lines assessed via NBDG uptake assay. Production of lactate was also significantly increased as assessed by colorimetric assay. We then became interested in possible alterations in metabolism downstream of increased glucose uptake. By Seahorse assay we found that IL-4 significantly increased glycolysis, as well as mitochondrial metabolism when assessed by ATP Rate assay. By metabolic flux using C13 labeled glucose we found that IL-4 increased incorporation of carbon from glucose into lactate while not having a significant effect on TCA cycle intermediates. This led us to question whether IL-4 may affect other arms of metabolism that feed into TCA cycle and mitochondrial metabolism. We looked at how IL4 impacts glutaminolysis and found that IL-4 stimulation leads to increased expression of glutamine transporter ASCT2, as well as increased glutamine uptake. We have begun to examine whether these metabolic changes affect epigenetic regulation. Initial data indicates that IL4 treatment leads to increased histone acetylation in TNBC cell lines. Citation Format: Demond Williams, Wendy Bindeman, Ebony Hargrove-Wiley, Barbara Fingleton. Interleukin-4 receptor signaling induces glycolysis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2381.