Tumor-Associated Macrophage-Derived Exosomes Regulate Glycolytic Reprogramming in Colorectal Cancer: Potential Involvement of the INHBB/SphK1/S1P Axis

Abstract

Exploring the Mechanism of Tumor-Associated Macrophage Exosomes (TAMs Exo) Regulating Colorectal Cancer (CRC) through Metabolic Reprogramming Induced by the INHBB/SphK1/S1P Axis. Method: By using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting (WB) testing of INHBB, TGF-β, and SphK1 were detected. Enzyme-linked immunosorbent assay (ELISA) was used to detect S1P levels. MTT assay assessed cell viability, and flow cytometry (FCM) evaluated cell apoptosis. The lactate determination kit and glucose determination kit measure lactate generation level and glucose uptake. The Transwell assay was utilized to evaluate the cellular migration capability. Result: The findings from the lactic acid and glucose reagent kit tests indicated that TAMs Exo augmented glycolytic processes in CRC cells and upregulated the expression of INHBB. The Cancer Genome Atlas (TCGA) analysis displayed that INHBB was highly expressed in CRC (P<0.001); TAMs Exo with low expression of INHBB significantly impeded the viability and migration of CRC cells, while concurrently enhancing their apoptosis (P<0.001). The analysis of pathway correlation revealed a strong positive association between INHBB and the expression level of the TGF-β signaling pathway's genes. Moreover, TAMs Exo with low expression of INHBB could suppress SphK1 expression and reduce S1P levels, downstream molecules within this pathway (P<0.001). Conclusion: TAMs Exo may induce glycolytic metabolic reprogramming in CRC by promoting the expression of INHBB in CRC cells, possibly via the SphK1/S1P axis, thereby promoting the development of CRC.