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

Abstract

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.

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Fig. 1: Proteomic and lipidomic changes in highly metastatic ovarian cancer cells.
Fig. 2: ACSL1 enhances ovarian cancer cell growth, spheroid formation, and tumorigenesis in a xenograft model.
Fig. 3: Target gene expression and MA treatment enhances the metastatic properties of NM cells.
Fig. 4: Myristoylation of Src and AMPKβ in HM and NM cells treated with MA or overexpressing ACSL1.
Fig. 5: MA treatment and ACSL1 expression activate the AMPK pathway and increase FAO in ovarian cancer cells.
Fig. 6: Inhibition of ACSL1 and NMT1 suppresses ovarian cancer progression and metastasis and the AMPK pathway.
Fig. 7: IHC staining in tissue microarray and clinical data suggest that high ACSL1 expression is associated with poor outcomes in patients with ovarian cancer.

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Acknowledgements

This work and LTOL were funded by The Science and Technology Development Fund, Macau SAR (File no. 0016/2020/A1) and University of Macau (File. no. MYRG2019-00075-FHS). ASTW was supported by Hong Kong Research Grant Council grant GRF17105919. We acknowledge the Animal Research Core Facility from University of Macau for their support in the animal experiments.

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QZ, WZ, YS, and LTOL designed and performed the experiments. YJ provided ovarian tumour specimens. ASTW and SKYT provided the isogenic cell lines and supported the xenograft experiments. TCWP and KYT guided the proteomic and metabolite analysis. QZ, WZ and LTOL wrote the paper and all authors reviewed the paper.

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Correspondence to Leo Tsz On Lee.

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Zhang, Q., Zhou, W., Yu, S. et al. Metabolic reprogramming of ovarian cancer involves ACSL1-mediated metastasis stimulation through upregulated protein myristoylation. Oncogene 40, 97–111 (2021). https://doi.org/10.1038/s41388-020-01516-4

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