Metabolic reprogramming of ovarian cancer involves ACSL1-mediated metastasis stimulation through upregulated protein myristoylation

• Published in: Oncogene 2021-01, Vol.40 (1), p.97-111
• Main Authors: Zhang, Qingyu, Zhou, Wei, Yu, Shan, Ju, Yaojun, To, Sally Kit Yan, Wong, Alice Sze Tsai, Jiao, Yufei, Poon, Terence Chuen Wai, Tam, Kin Yip, Lee, Leo Tsz On
• Format: Article
• Language: English
• Subjects: 13/106; 13/51; 45/90; 631/67/1517/1709; 631/67/2327; 64/60; 82/58; 82/80; 96/95; AMP; AMP-activated protein kinase; Animals; Apoptosis; Carcinoma, Ovarian Epithelial - metabolism; Carcinoma, Ovarian Epithelial - pathology; Care and treatment; Cell Biology; Cell Line, Tumor; Cellular proteins; Coenzyme A Ligases - metabolism; Complications and side effects; Fatty Acids - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Lipid metabolism; Lipidomics; Medicine; Medicine & Public Health; Metabolism; Metastases; Metastasis; Mice; Microenvironments; Myristoylation; Neoplasm Metastasis; Neoplasm Transplantation; Omentum; Oncology; Ovarian cancer; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Oxidation; Phospholipids; Prognosis; Proteins; Proteomics - methods; Risk factors; Signal Transduction; Tumor Microenvironment; Tumors; Up-Regulation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01516-4

As a result of the hostile microenvironment, metabolic alterations are required to enable the malignant growth of cancer cells. To understand metabolic reprogramming during metastasis, we conducted shotgun proteomic analysis of highly metastatic (HM) and non-metastatic (NM) ovarian cancer cells. The results suggest that the genes involved in fatty-acid (FA) metabolism are upregulated, with consequent increases of phospholipids with relatively short FA chains (myristic acid, MA) in HM cells. Among the upregulated proteins, ACSL1 expression could convert the lipid profile of NM cells to that similar of HM cells and make them highly aggressive. Importantly, we demonstrated that ACSL1 activates the AMP-activated protein kinase and Src pathways via protein myristoylation and finally enhances FA beta oxidation. Patient samples and tissue microarray data also suggested that omentum metastatic tumours have higher ACSL1 expression than primary tumours and a strong association with poor clinical outcome. Overall, our data reveal that ACSL1 enhances cancer metastasis by regulating FA metabolism and myristoylation.