Stromal-epithelial lactate shuttle induced by tumor-derived interleukin-1β promotes cell proliferation in oral squamous cell carcinoma

Stromal-epithelial lactate shuttle is an essential process to support fast-growing tumor cells, however, the underlying mechanism remains ambiguous. Interleukin-1β (IL-1β), which is a key node gene in both stromal and epithelial cells of oral squamous cell carcinoma (OSCC), may participate in this metabolic reprogramming. In the present study, anaerobic glycolysis of cancer-associated fibroblasts (CAFs) was evaluated and the role of IL-1β in regulating stromal-epithelial lactate shuttle was determined. A co-culture system of primary fibroblasts and OSCC cell lines (CAL27, UM1 or SCC25) was created to investigate the stromal-epithelial interaction. α-smooth muscle actin (α-SMA) expression of fibroblasts, IL-1β expression and cell proliferation of OSCC cells, and a series of glycolytic genes were measured. Recombinant IL-1β treatment and IL-1β knockdown in UM1 cells were also used to evaluate the effect of IL-1β. Expression of α-SMA, glucose transporter 1, hexokinase 2, lactic dehydrogenase and mono-carboxylate transporter (MCT) 4 were significantly overexpressed in activated fibroblasts, while IL-1β and MCT1 were upregulated in OSCC cells, indicating enhanced glycolysis in cells of the tumor stroma and a lactate shuttle to the tumor cells. Furthermore, exogenous IL-1β induced fibroblasts to present similar expression profiles as that in the co-culture system. Silencing of IL-1β significantly abrogated the regulatory effect of UM1 cells on stromal glycolysis. Additionally, carboxy-fluorescein succinimidyl ester cell tracing indicated that OSCC cell proliferation was accelerated during co-cultivation with fibroblasts. These results indicate that tumor-derived IL-1β enhanced stromal glycolysis and induced one-way lactate flow from the tumor mesenchyme to transformed epithelium, which promotes OSCC proliferation.