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

Abstract

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.

As a Novel Tumor Suppressor, LHPP Promotes Apoptosis by Inhibiting the PI3K/AKT Signaling Pathway in Oral Squamous Cell Carcinoma

“…In recent years, many advances have been made in the role of PI3K/AKT inhibitors in OSCC. For example, PI3K inhibitors could promote the apoptotic activity of the anticancer drugs cisplatin, 5-fluorouracil or docetaxel in OSCC cell lines [32,33]. PI3K inhibitors such as PI-103, PI-828 and PX-866 may be developed as potential therapeutic agents for effective treatment of OSCC patients [34].…”

The Immuno-Modulation Effect of Macrophage-Derived Extracellular Vesicles in Chronic Inflammatory Diseases

“…However, it is unclear whether they contain functional endogenous DNA. In oral squamous cell carcinoma, THP-1-derived EVs and native human Mφ-derived EVs have been shown to activate the AKT/GSK-3β signaling pathway, reducing the proliferative effects of 5-FU and cis−diamminedichloroplatinum (CDDP) and the apoptosis of OSC-4 cells ( 165 ).…”

Impact of Non-Coding RNAs on Chemotherapeutic Resistance in Oral Cancer

“…Depletion of exosomal miR-196a restored cisplatin sensitivity in head and neck cancer cells. In contrast, normal cell-derived EVs have the potential to suppress tumor progression [ 212 , 213 , 214 , 215 ]. Notably, miR-200c was packaged into EVs derived from normal tongue epithelial cells (NTECs), which were transferred into docetaxel-resistant cells, and the transferred miR-200c influenced docetaxel resistance by inhibiting TUBB3 and PPP2R1B [ 212 ].…”