Enhanced lipid biosynthesis in OSCC cancer associated fibroblasts contributes to tumor progression: role of IL8/AKT/p-ACLY axis

Abstract Background ATP citrate lygase (ACLY), the key enzyme regulating lipid synthesis, has been proven to play a critical role in tumor initiation and development. However, the roles and relevant mechanisms of ACLY in cancer associated fibroblasts (CAFs) have rarely been studied, particularly in CAFs of oral squamous cell carcinoma (OSCC). Plus, the molecular mechanism by which tumor cells regulate ACLY in fibroblasts is unclear. Methods IHC staining, PCR and Western blot were employed to detect ACLY expression pattern in OSCC tissues and OSCC primary CAFs. The biological roles and relevant mechanisms of ACLY in OSCC CAFs were investigated by in vitro and in vivo experiments. Results The phosphorylated ACLY (p-ACLY) was highly expressed in OSCC CAFs and CAFs underwent enhanced lipid synthesis, including elevated intracellular level of acetyl-CoA and accumulation of lipid droplets. Conversely, inhibition of p-ACLY blocked this biological process. Moreover, blocking lipid synthesis in CAFs or inhibiting fatty acid uptake by OSCC cells reduced the promotive effects of CAFs on OSCC cell proliferation, invasion and migration. These results suggested that CAFs served as one of lipid sources for OSCC cells during tumor progression. Mechanistically, AKT signaling activation was involved in the elevations of p-ACLY level and lipid synthesis in CAFs. IL8 was an exocrine cytokine of OSCC cells that could activate AKT and then phosphorylate ACLY in fibroblasts. Conclusions P-ACLY positively regulated lipid synthesis of OSCC CAFs, making CAFs one of the lipid sources required for tumor progression. IL8 was an exocrine cytokine of OSCC cells that could upregulate p-ACLY level and lipid synthesis in fibroblasts via AKT signaling activation. Therefore, the IL8/AKT/p-ACLY axis could be considered as a potential therapeutic target for OSCC treatment.