Letter to the editor
LIPG supports adaption to oxidative stress
Gregor Leonhardt11Leibniz Research Centre for Working Environment and Human Factors
EXCLI J 2019;18:Doc499
Recently, Cadenas and colleagues reported that the endothelial lipase (LIPG) is upregulated during oxidative stress and supports survival of cells that are no longer able to generate a sufficient supply of fatty acids by de novo synthesis (Cadenas et al., 2019). LIPG is a cell surface associated lipase that cleaves phosphatidylcholine from high-density lipoproteins (Jaye et al., 1999; Choi et al., 2002). Thereby, free fatty acids are released that can be taken up by cells (Riederer et al., 2012). It has also been shown that overexpression of an oncogenic form of erbB2 leads to strong expression of LIPG (Cadenas et al., 2012) and LIPG has been reported to be associated with tumor growth (Slebe et al., 2016) and with metastasis in triple-negative breast cancer (Lo et al., 2018).
In the present study, Cadenas and colleagues used overexpression and knockdown strategies to demonstrate that LIPG enables breast cancer cell lines to utilize circulating lipoproteins to synthetize and store triglycerides in lipid droplets (Cadenas et al., 2019). Moreover, the authors showed that oxidative stress under conditions that block endogenous fatty acid synthesis induces LIPG expression and activity. Induction of LIPG was also observed after pharmacological inhibition of de novo fatty acid synthesis (Cadenas et al., 2019). A key observation of the present study is that LIPG upregulation protects the cells from mitochondrial dysfunction and cell death. Finally, analyzing expression data of more than 1,000 breast carcinomas, Cadenas and colleagues showed that a small fraction of tumors overexpresses LIPG which was associated with shorter metastasis-free survival.
Progression of tumors is a complex process that involves genes controlling proliferation (Schmidt et al., 2008), immune cell infiltration (Schmidt et al., 2012; 2018; Heimes et al., 2017; Edlund et al., 2019), redox status (Cadenas et al., 2010), metabolism (Hellwig et al., 2016; Marchan et al., 2017; Stewart et al., 2012) and circadian rhythm (Cadenas et al., 2014) and several more. It is clear that carcinomas have to adapt to conditions of hypoxia and oxidative stress (Spangenberg et al., 2006). LIPG upregulation seems to be one of the mechanisms how cancer cells can guarantee fatty acid supply from extracellular sources under conditions where oxidative stress blocks endogenous synthesis.
1. Cadenas C, Franckenstein D, Schmidt M, Gehrmann M, Hermes M, Geppert B, et al. Role of thioredoxin reductase 1 and thioredoxin interacting protein in prognosis of breast cancer. Breast Cancer Res. 2010;12:R44.
2. Cadenas C, van de Sandt L, Edlund K, Lohr M, Hellwig B, Marchan R, et al. Loss of circadian clock gene expression is associated with tumor progression in breast cancer. Cell Cycle. 2014;13:3282-91.
3. Cadenas C, Vosbeck S, Edlund K, Grgas K, Madjar K, Hellwig B, et al. LIPG-promoted lipid storage mediates adaptation to oxidative stress in breast cancer. Int J Cancer. 2019;145:901-15.
4. Cadenas C, Vosbeck S, Hein EM, Hellwig B, Langer A, Hayen H, et al.. Glycerophospholipid profile in oncogene-induced senescence. Biochim Biophys Acta. 2012;1821:1256-68.
5. Choi SY, Hirata K, Ishida T, Quertermous T, Cooper AD. Endothelial lipase: a new lipase on the block. J Lipid Res. 2002;43:1763-9.
6. Edlund K, Madjar K, Mattsson JSM, Djureinovic D, Lindskog C, Brunnström H, et al. Prognostic impact of tumor cell programmed death ligand 1 expression and immune cell infiltration in NSCLC. J Thorac Oncol. 2019;14:628-40.
7. Heimes AS, Madjar K, Edlund K, Battista MJ, Almstedt K, Elger T, et al. Subtype-specific prognostic impact of different immune signatures in node-negative breast cancer. Breast Cancer Res Treat. 2017;165:293-300.
8. Heimes AS, Madjar K, Edlund K, Battista MJ, Almstedt K, Gebhard S, et al. Prognostic significance of interferon regulating factor 4 (IRF4) in node-negative breast cancer. J Cancer Res Clin Oncol. 2017;143:1123-31.
9. Hellwig B, Madjar K, Edlund K, Marchan R, Cadenas C, Heimes AS, et al. Epsin family member 3 and ribosome-related genes are associated with late metastasis in estrogen receptor-positive breast cancer and long-term survival in non-small cell lung cancer using a genome-wide identification and validation strategy. PLoS One. 2016;11(12):e0167585.
10. Jaye M, Lynch KJ, Krawiec J, Marchadier D, Maugeais C, Doan K, et al. A novel endothelial-derived lipase that modulates HDL metabolism. Nat Genet. 1999;21:424-8.
11. Lo PK, Yao Y, Lee JS, Zhang Y, Huang W, Kane MA, et al. LIPG signaling promotes tumor initiation and metastasis of human basal-like triple-negative breast cancer. eLife. 2018;7:e31334.
12. Marchan R, Büttner B, Lambert J, Edlund K, Glaeser I, Blaszkewicz M, et al. Glycerol-3-phosphate acyltransferase 1 promotes tumor cell migration and poor survival in ovarian carcinoma. Cancer Res. 2017;77:4589-601.
13. Riederer M, Köfeler H, Lechleitner M, Tritscher M, Frank S. Impact of endothelial lipase on cellular lipid composition. Biochim Biophys Acta. 2012;1821:1003–11.
14. Schmidt M, Böhm D, von Törne C, Steiner E, Puhl A, Pilch H, et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68:5405-13.
15. Schmidt M, Hellwig B, Hammad S, Othman A, Lohr M, Chen Z, et al. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin κ C as a compatible prognostic marker in human solid tumors. Clin Cancer Res. 2012;18:2695-703.
16. Schmidt M, Weyer-Elberich V, Hengstler JG, Heimes AS, Almstedt K, Gerhold-Ay A, et al. Prognostic impact of CD4-positive T cell subsets in early breast cancer: a study based on the FinHer trial patient population. Breast Cancer Res. 2018;20(1):15.
17. Slebe F, Rojo F, Vinaixa M, García-Rocha M, Testoni G, Guiu M, et al. FoxA and LIPG endothelial lipase control the uptake of extracellular lipids for breast cancer growth. Nat Commun. 2016;7:11199.
18. Spangenberg C, Lausch EU, Trost TM, Prawitt D, May A, Keppler R, et al. ERBB2-mediated transcriptional up-regulation of the alpha5beta1 integrin fibronectin receptor promotes tumor cell survival under adverse conditions. Cancer Res. 2006;66:3715-25.
19. Stewart JD, Marchan R, Lesjak MS, Lambert J, Hergenroeder R, Ellis JK, et al. Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis. Proc Natl Acad Sci U S A. 2012;109:8155-60.