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Breast Cancer
Published in: Breast Cancer 4/2020

01-07-2020 | Breast Cancer | Original Article

SCD1 activity promotes cell migration via a PLD-mTOR pathway in the MDA-MB-231 triple-negative breast cancer cell line

Authors: Marine Lingrand, Simon Lalonde, Antoine Jutras-Carignan, Karl-F. Bergeron, Eric Rassart, Catherine Mounier

Published in: Breast Cancer | Issue 4/2020

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Abstract

Background

Breast cancer is the most common cancer in women. Despite high survival rates in Western countries, treatments are less effective in metastatic cases and triple-negative breast cancer (TNBC) patient survival is the shortest across breast cancer subtypes. High expression levels of stearoyl-CoA desaturase-1 (SCD1) have been reported in breast cancer. The SCD1 enzyme catalyzes the formation of oleic acid (OA), a lipid stimulating the migration of metastatic breast cancer cells. Phospholipase activity is also implicated in breast cancer metastasis, notably phospholipase D (PLD).

Methods

Kaplan–Meier survival plots generated from gene expression databases were used to analyze the involvement of SCD1 and PLD in several cancer subtypes. SCD1 enzymatic activity was modulated with a pharmaceutical inhibitor or by OA treatment (to mimic SCD1 over-activity) in three breast cancer cell lines: TNBC-derived MDA-MB-231 cells as well as non-TNBC MCF-7 and T47D cells. Cell morphology and migration properties were characterized by various complementary methods.

Results

Our survival analyses suggest that SCD1 and PLD2 expression in the primary tumor are both associated to metastasis-related morbid outcomes in breast cancer patients. We show that modulation of SCD1 activity is associated with the modification of TNBC cell migration properties, including changes in speed, direction and cell morphology. Cell migration properties are regulated by SCD1 activity through a PLD-mTOR/p70S6K signaling pathway. These effects are not observed in non-TNBC cell lines.

Conclusion

Our results establish a key role for the lipid desaturase SCD1 and delineate an OA-PLD-mTOR/p70S6K signaling pathway in TNBC-derived MDA-MB-231 cell migration.
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Literature
1.
Kwan ML, et al. Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors. Breast Cancer Res. 2009;11(3):R31.PubMedPubMedCentralCrossRef
2.
Hudis CA, Gianni L. Triple-negative breast cancer: an unmet medical need. Oncologist. 2011;16(Suppl 1):1–11.PubMedCrossRef
3.
Gunasinghe NP, et al. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 2012;31(3–4):469–78.PubMedCrossRef
4.
Saunus JM, et al. Breast cancer brain metastases: clonal evolution in clinical context. Int J Mol Sci. 2017;18:1.CrossRef
5.
Igal RA. Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis. 2010;31(9):1509–15.PubMedCrossRef
6.
Igal RA. Roles of StearoylCoA desaturase-1 in the regulation of cancer cell growth survival and tumorigenesis. Cancers (Basel). 2011;3(2):2462–77.CrossRef
7.
Chajes V, et al. Fatty-acid composition in serum phospholipids and risk of breast cancer: an incident case-control study in Sweden. Int J Cancer. 1999;83(5):585–90.PubMedCrossRef
8.
Guo S, et al. Significantly increased monounsaturated lipids relative to polyunsaturated lipids in six types of cancer microenvironment are observed by mass spectrometry imaging. Sci Rep. 2014;4:5959.PubMedPubMedCentralCrossRef
9.
10.
Huang GM, et al. SCD1 negatively regulates autophagy-induced cell death in human hepatocellular carcinoma through inactivation of the AMPK signaling pathway. Cancer Lett. 2015;358(2):180–90.PubMedCrossRef
11.
12.
Fritz V, et al. Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice. Mol Cancer Ther. 2010;9(6):1740–54.PubMedPubMedCentralCrossRef
13.
von Roemeling CA, et al. Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Clin Cancer Res. 2013;19(9):2368–80.CrossRef
14.
Ide Y, et al. Human breast cancer tissues contain abundant phosphatidylcholine(36ratio1) with high stearoyl-CoA desaturase-1 expression. PLoS ONE. 2013;8(4):e61204.PubMedPubMedCentralCrossRef
15.
Scaglia N, Chisholm JW, Igal RA. Inhibition of stearoylCoA desaturase-1 inactivates acetyl-CoA carboxylase and impairs proliferation in cancer cells: role of AMPK. PLoS ONE. 2009;4(8):e6812.PubMedPubMedCentralCrossRef
16.
Nashed M, Chisholm JW, Igal RA. Stearoyl-CoA desaturase activity modulates the activation of epidermal growth factor receptor in human lung cancer cells. Exp Biol Med (Maywood). 2012;237(9):1007–17.CrossRef
17.
Holder AM, et al. High stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients. Breast Cancer Res Treat. 2013;137(1):319–27.PubMedCrossRef
18.
Peck B, et al. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments. Cancer Metab. 2016;4:6.PubMedPubMedCentralCrossRef
19.
Mauvoisin D, et al. Decreasing stearoyl-CoA desaturase-1 expression inhibits beta-catenin signaling in breast cancer cells. Cancer Sci. 2013;104(1):36–42.PubMedCrossRef
20.
Navarro-Tito N, et al. Oleic acid promotes migration on MDA-MB-231 breast cancer cells through an arachidonic acid-dependent pathway. Int J Biochem Cell Biol. 2010;42(2):306–17.PubMedCrossRef
21.
Soto-Guzman A, et al. Oleic acid induces ERK1/2 activation and AP-1 DNA binding activity through a mechanism involving Src kinase and EGFR transactivation in breast cancer cells. Mol Cell Endocrinol. 2008;294(1–2):81–91.PubMedCrossRef
22.
Hardy S, et al. Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40. J Biol Chem. 2005;280(14):13285–91.PubMedCrossRef
23.
Sliva D, et al. Enhancement of the migration of metastatic human breast cancer cells by phosphatidic acid. Biochem Biophys Res Commun. 2000;268(2):471–9.PubMedCrossRef
24.
Zheng Y, et al. Phospholipase D couples survival and migration signals in stress response of human cancer cells. J Biol Chem. 2006;281(23):15862–8.PubMedCrossRef
25.
Henkels KM, et al. Phospholipase D (PLD) drives cell invasion, tumor growth and metastasis in a human breast cancer xenograph model. Oncogene. 2013;32(49):5551–62.PubMedPubMedCentralCrossRef
26.
Sarri E, et al. Endogenous phospholipase D2 localizes to the plasma membrane of RBL-2H3 mast cells and can be distinguished from ADP ribosylation factor-stimulated phospholipase D1 activity by its specific sensitivity to oleic acid. Biochem J. 2003;369(Pt 2):319–29.PubMedPubMedCentralCrossRef
27.
Kim JH, et al. Selective activation of phospholipase D2 by unsaturated fatty acid. FEBS Lett. 1999;454(1–2):42–6.PubMedCrossRef
28.
29.
Knoepp SM, et al. Effects of active and inactive phospholipase D2 on signal transduction, adhesion, migration, invasion, and metastasis in EL4 lymphoma cells. Mol Pharmacol. 2008;74(3):574–84.PubMedCrossRef
30.
Gyorffy B, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123(3):725–31.PubMedCrossRef
31.
Angelucci C, et al. Pivotal role of human stearoyl-CoA desaturases (SCD1 and 5) in breast cancer progression: oleic acid-based effect of SCD1 on cell migration and a novel pro-cell survival role for SCD5. Oncotarget. 2018;9(36):24364–80.PubMedPubMedCentralCrossRef
32.
Tracz-Gaszewska Z, Dobrzyn P. Stearoyl-CoA desaturase 1 as a therapeutic target for the treatment of cancer. Cancers (Basel). 2019;11:7.CrossRef
33.
Clark AG, Vignjevic DM. Modes of cancer cell invasion and the role of the microenvironment. Curr Opin Cell Biol. 2015;36:13–22.PubMedCrossRef
34.
35.
36.
Toschi A, et al. Regulation of mTORC1 and mTORC2 complex assembly by phosphatidic acid: competition with rapamycin. Mol Cell Biol. 2009;29(6):1411–20.PubMedCrossRef
37.
Costa RLB, Han HS, Gradishar WJ. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat. 2018;169(3):397–406.PubMedCrossRef
38.
Lavieri R, et al. Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors Part II Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity. Bioorg Med Chem Lett. 2009;19(8):2240–3.PubMedPubMedCentralCrossRef
39.
40.
Angelucci C, et al. Stearoyl-CoA desaturase 1 and paracrine diffusible signals have a major role in the promotion of breast cancer cell migration induced by cancer-associated fibroblasts. Br J Cancer. 2015;112(10):1675–86.PubMedPubMedCentralCrossRef
41.
Miyazaki M, et al. Oleoyl-CoA is the major de novo product of stearoyl-CoA desaturase 1 gene isoform and substrate for the biosynthesis of the Harderian gland 1-alkyl-2,3-diacylglycerol. J Biol Chem. 2001;276(42):39455–61.PubMedCrossRef
42.
Rios-Esteves J, Resh MD. Stearoyl CoA desaturase is required to produce active, lipid-modified Wnt proteins. Cell Rep. 2013;4(6):1072–81.PubMedCrossRef
43.
44.
Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3(5):362–74.PubMedCrossRef
45.
46.
Friedl P, Alexander S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell. 2011;147(5):992–1009.PubMedCrossRef
47.
Miyazaki M, et al. The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1. J Biol Chem. 2000;275(39):30132–8.PubMedCrossRef
48.
49.
50.
Igal RA. Stearoyl CoA desaturase-1: new insights into a central regulator of cancer metabolism. Biochim Biophys Acta. 2016;1861(12 Pt A):1865–80.PubMedCrossRef
51.
Chen Y, Zheng Y, Foster DA. Phospholipase D confers rapamycin resistance in human breast cancer cells. Oncogene. 2003;22(25):3937–42.PubMedCrossRef
52.
53.
Cazzolli R, et al. Phospholipid signalling through phospholipase D and phosphatidic acid. IUBMB Life. 2006;58(8):457–61.PubMedCrossRef
54.
de Brachene AC, et al. PDGF-induced fibroblast growth requires monounsaturated fatty acid production by stearoyl-CoA desaturase. FEBS Open Bio. 2017;7(3):414–23.CrossRef
55.
Navarro-Tito N, Robledo T, Salazar EP. Arachidonic acid promotes FAK activation and migration in MDA-MB-231 breast cancer cells. Exp Cell Res. 2008;314(18):3340–55.PubMedCrossRef
Metadata
Title
SCD1 activity promotes cell migration via a PLD-mTOR pathway in the MDA-MB-231 triple-negative breast cancer cell line
Authors
Marine Lingrand
Simon Lalonde
Antoine Jutras-Carignan
Karl-F. Bergeron
Eric Rassart
Catherine Mounier
Publication date
01-07-2020
Publisher
Springer Japan
Published in
Breast Cancer / Issue 4/2020
Print ISSN: 1340-6868
Electronic ISSN: 1880-4233
DOI
https://doi.org/10.1007/s12282-020-01053-8

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