Macrophage-derived exosomes attenuate the susceptibility of oral squamous cell carcinoma cells to chemotherapeutic drugs through the AKT/GSK-3β pathway

Although chemotherapy is initially effective in debulking tumor mass in a number of different types of malignancy, tumor cells gradually acquire chemoresistance and frequently progress to advanced clinical stage. Accumulating evidence has indicated that the tumor sensitivity to several chemotherapeutic drugs is regulated by tumor stromal cells including macrophages. However, the role of macrophages in the efficacy of chemotherapeutics on oral squamous cell carcinoma (OSCC) cells is poorly understood. In the present study, the effects of macrophage-secreted exosomes on the sensitivity of OSCC cells towards chemotherapeutic agents were examined. Specifically, the effects of exosomes derived from THP-1 cells and primary human macrophages (PHM) were assessed on the chemosensitivity of OSC-4 cells treated with 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum (CDDP). The THP-1- and PHM-derived exosomes promoted dose-dependent proliferation, decreased the proliferative inhibitory effects of 5-FU and CDDP and decreased apoptosis in OSC-4 cells through activation of the AKT/glycogen synthase kinase-3β signaling pathway. LY294002, a PI3K inhibitor, and MK-2206, an AKT inhibitor, were both able to suppress the observed decrease in sensitivity to chemotherapeutic agents induced by exosomes. Overall, the data from the present study suggested that the macrophage-derived exosomes may decrease the sensitivity to chemotherapeutic agents in OSCC cells. Thus, targeting the interaction between OSCC cells and macrophage-derived exosomes may be considered as a therapeutic approach to improve the chemosensitivity of the tumor microenvironment in oral cancer.