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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References
Dirat B, Bochet L, Escourrou G, Valet P, Muller C. Unraveling the obesity and breast cancer links: a role for cancer-associated adipocytes? Endocr Dev. 2010;19:45–52.
Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.
Pradeep S, Kim SW, Wu SY, Nishimura M, Chaluvally-Raghavan P, Miyake T, et al. Hematogenous metastasis of ovarian cancer: rethinking mode of spread. Cancer Cell. 2014;26:77–91.
Tucker SL, Gharpure K, Herbrich SM, Unruh AK, Nick AM, Crane EK, et al. Molecular biomarkers of residual disease after surgical debulking of high-grade serous ovarian cancer. Clin Cancer Res. 2014;20:3280–8.
Resh MD. Covalent lipid modifications of proteins. Curr Biol. 2013;23:R431–5.
Liang J, Xu ZX, Ding Z, Lu Y, Yu Q, Werle KD, et al. Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance. Nat Commun. 2015;6:7926.
Udenwobele DI, Su RC, Good SV, Ball TB, Varma Shrivastav S, Shrivastav A. Myristoylation: an Important protein modification in the immune response. Front Immunol. 2017;8:751.
Dian C, Perez-Dorado I, Riviere F, Asensio T, Legrand P, Ritzefeld M, et al. High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation. Nat Commun. 2020;11:1132.
Kim S, Yang X, Li Q, Wu M, Costyn L, Beharry Z, et al. Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice. J Biol Chem. 2017;292:18422–33.
To SKY, Mak ASC, Eva Fung YM, Che CM, Li SS, Deng W, et al. beta-catenin downregulates Dicer to promote ovarian cancer metastasis. Oncogene. 2017;36:5927–38.
Patwardhan P, Resh MD. Myristoylation and membrane binding regulate c-Src stability and kinase activity. Mol Cell Biol. 2010;30:4094–107.
Kim S, Alsaidan OA, Goodwin O, Li Q, Sulejmani E, Han Z, et al. Blocking myristoylation of Src inhibits its kinase activity and suppresses prostate cancer progression. Cancer Res. 2017;77:6950–62.
Lobo S, Wiczer BM, Bernlohr DA. Functional analysis of long-chain acyl-CoA synthetase 1 in 3T3-L1 adipocytes. J Biol Chem. 2009;284:18347–56.
Tang Y, Zhou J, Hooi SC, Jiang YM, Lu GD. Fatty acid activation in carcinogenesis and cancer development: essential roles of long-chain acyl-CoA synthetases. Oncol Lett. 2018;16:1390–6.
Sanchez-Martinez R, Cruz-Gil S, Garcia-Alvarez MS, Reglero G, Ramirez, de Molina A. Complementary ACSL isoforms contribute to a non-Warburg advantageous energetic status characterizing invasive colon cancer cells. Sci Rep. 2017;7:11143.
Wang Y, Cai X, Zhang S, Cui M, Liu F, Sun B, et al. HBXIP up-regulates ACSL1 through activating transcriptional factor Sp1 in breast cancer. Biochem Biophys Res Commun. 2017;484:565–71.
Cui M, Wang Y, Sun B, Xiao Z, Ye L, Zhang X. MiR-205 modulates abnormal lipid metabolism of hepatoma cells via targeting acyl-CoA synthetase long-chain family member 1 (ACSL1) mRNA. Biochem Biophys Res Commun. 2014;444:270–5.
Yen MC, Kan JY, Hsieh CJ, Kuo PL, Hou MF, Hsu YL. Association of long-chain acyl-coenzyme A synthetase 5 expression in human breast cancer by estrogen receptor status and its clinical significance. Oncol Rep. 2017;37:3253–60.
Thinon E, Serwa RA, Broncel M, Brannigan JA, Brassat U, Wright MH, et al. Global profiling of co- and post-translationally N-myristoylated proteomes in human cells. Nat Commun. 2014;5:4919.
Aebersold R, Mann M. Mass-spectrometric exploration of proteome structure and function. Nature. 2016;537:347–55.
Das U, Kumar S, Dimmock JR, Sharma RK. Inhibition of protein N-myristoylation: a therapeutic protocol in developing anticancer agents. Curr Cancer Drug Targets. 2012;12:667–92.
Jeon SM, Hay N. The dark face of AMPK as an essential tumor promoter. Cell Logist. 2012;2:197–202.
Oakhill JS, Chen ZP, Scott JW, Steel R, Castelli LA, Ling N, et al. beta-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc Natl Acad Sci USA. 2010;107:19237–41.
Viollet B, Foretz M, Guigas B, Horman S, Dentin R, Bertrand L, et al. Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J Physiol. 2006;574:41–53.
Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med. 2013;19:1649–54.
Lopez-Mejia IC, Lagarrigue S, Giralt A, Martinez-Carreres L, Zanou N, Denechaud PD, et al. CDK4 phosphorylates AMPKalpha2 to inhibit its activity and repress fatty acid oxidation. Mol Cell. 2017;68:336–49. e336.
Carracedo A, Cantley LC, Pandolfi PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer. 2013;13:227–32.
Pike LS, Smift AL, Croteau NJ, Ferrick DA, Wu M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim Biophys Acta. 2011;1807:726–34.
Mizrachy-Schwartz S, Cohen N, Klein S, Kravchenko-Balasha N, Levitzki A. Up-regulation of AMP-activated protein kinase in cancer cell lines is mediated through c-Src activation. J Biol Chem. 2011;286:15268–77.
Zou M-H, Hou X-Y, Shi C-M, Kirkpatick S, Liu F, Goldman MH, et al. Activation of 5′-AMP-activated kinase is mediated through c-Src and phosphoinositide 3-kinase activity during hypoxia-reoxygenation of bovine aortic endothelial cells Role of peroxynitrite. J Biol Chem. 2003;278:34003–10.
Anbalagan M, Moroz K, Ali A, Carrier L, Glodowski S, Rowan BG. Subcellular localization of total and activated Src kinase in African American and Caucasian breast cancer. PloS ONE. 2012;7:e33017.
Tryfonopoulos D, Walsh S, Collins DM, Flanagan L, Quinn C, Corkery B, et al. Src: a potential target for the treatment of triple-negative breast cancer. Ann Oncol. 2011;22:2234–40.
Park JH, Vithayathil S, Kumar S, Sung PL, Dobrolecki LE, Putluri V, et al. Fatty acid oxidation-driven Src links mitochondrial energy reprogramming and oncogenic properties in triple-negative breast cancer. Cell Rep. 2016;14:2154–65.
Pengetnze Y, Steed M, Roby KF, Terranova PF, Taylor CC. Src tyrosine kinase promotes survival and resistance to chemotherapeutics in a mouse ovarian cancer cell line. Biochem Biophys Res Commun. 2003;309:377–83.
Wiener JR, Windham TC, Estrella VC, Parikh NU, Thall PF, Deavers MT, et al. Activated SRC protein tyrosine kinase is overexpressed in late-stage human ovarian cancers. Gynecol Oncol. 2003;88:73–9.
Deng L, Gao X, Liu B, He X, Xu J, Qiang J, et al. NMT1 inhibition modulates breast cancer progression through stress-triggered JNK pathway. Cell Death Dis. 2018;9:1143.
Thinon E, Morales-Sanfrutos J, Mann DJ, Tate EW. N-myristoyltransferase inhibition induces ER-stress, cell cycle arrest, and apoptosis in cancer cells. ACS Chem Biol. 2016;11:2165–76.
Sulejmani E, Cai H. Targeting protein myristoylation for the treatment of prostate cancer. Oncoscience. 2018;5:3–5.
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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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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DOI: https://doi.org/10.1038/s41388-020-01516-4
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