Enhanced lipid biosynthesis in oral squamous cell carcinoma cancer-associated fibroblasts contributes to tumor progression: Role of IL8/AKT/p-ACLY axis

• Published in: Cancer science 2024-05, Vol.115 (5), p.1433-1445
• Main Authors: Liu, Pan, Wang, Yue, Li, Xiang, Liu, Zhenan, Sun, Yunqing, Liu, Hanzhe, Shao, Zhe, Jiang, Erhui, Zhou, Xiaocheng, Shang, Zhengjun
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; ATP Citrate (pro-S)-Lyase - metabolism; ATP citrate lyase; Biosynthesis; Cancer; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Disease Progression; Fatty acids; Fibroblasts; Humans; Interleukin 8; Interleukin-8 - metabolism; Lipid Metabolism; Lipids; Male; Medical prognosis; Melanoma; Metabolism; Metabolites; Metastasis; Mice; Molecular modelling; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Ontology; Oral carcinoma; Oral squamous cell carcinoma; Original; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Quantitative analysis; Signal Transduction; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Tumor cells; Tumors; Up-Regulation
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.16111

Lipid metabolic reprogramming of tumor cells has been proven to play a critical role in tumor initiation and development. However, lipid metabolism in cancer-associated fibroblasts (CAFs) has rarely been studied, particularly in CAFs of oral squamous cell carcinoma (OSCC). Additionally, the molecular mechanism by which tumor cells regulate lipid metabolism in fibroblasts is unclear. In this study, we found that phosphorylated ATP citrate lyase (p-ACLY), a key lipid metabolic enzyme, was upregulated in OSCC CAFs. Compared to paracancerous normal fibroblasts, CAFs showed enhanced lipid synthesis, such as elevated cytosolic acetyl-CoA level and accumulation of lipid droplets. Conversely, reduction of p-ACLY level blocked this biological process. In addition, 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 findings suggested that CAFs are one of lipid sources required for OSCC progression. Mechanistically, AKT signaling activation was involved in the upregulation of p-ACLY level and lipid synthesis in CAFs. Interleukin-8 (IL8), an exocrine cytokine of OSCC cells, could activate AKT and then phosphorylate ACLY in fibroblasts. This study suggested that the IL8/AKT/p-ACLY axis could be considered as a potential target for OSCC treatment.