2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer.
Androgen Receptor Antagonists
/ administration & dosage
Disease Progression
Homeostasis
Humans
Lipid Metabolism
Male
Mitochondria
/ enzymology
Oxidoreductases Acting on CH-CH Group Donors
/ genetics
Phospholipids
/ metabolism
Prostate
/ enzymology
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Receptors, Androgen
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 05 2020
19 05 2020
Historique:
received:
08
08
2019
accepted:
24
03
2020
entrez:
20
5
2020
pubmed:
20
5
2020
medline:
25
8
2020
Statut:
epublish
Résumé
Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we perform a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicate an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism. To exploit this phenotype, we delineate a subset of proteins consistently associated with ARI resistance and highlight mitochondrial 2,4-dienoyl-CoA reductase (DECR1), an auxiliary enzyme of beta-oxidation, as a clinically relevant biomarker for CRPC. Mechanistically, DECR1 participates in redox homeostasis by controlling the balance between saturated and unsaturated phospholipids. DECR1 knockout induces ER stress and sensitises CRPC cells to ferroptosis. In vivo, DECR1 deletion impairs lipid metabolism and reduces CRPC tumour growth, emphasizing the importance of DECR1 in the development of treatment resistance.
Identifiants
pubmed: 32427840
doi: 10.1038/s41467-020-16126-7
pii: 10.1038/s41467-020-16126-7
pmc: PMC7237503
doi:
Substances chimiques
Androgen Receptor Antagonists
0
Phospholipids
0
Receptors, Androgen
0
Oxidoreductases Acting on CH-CH Group Donors
EC 1.3.-
2,4-dienoyl-CoA reductase
EC 1.3.1.34
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2508Subventions
Organisme : Cancer Research UK
ID : A15151
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C596/A17196
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A12935
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L017997/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 15151
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 300444-01
Pays : United Kingdom
Références
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. Cancer J. Clin. 68, 7–30 (2018).
doi: 10.3322/caac.21442
Watson, P. A., Arora, V. K. & Sawyers, C. L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer 15, 701–711 (2015).
pubmed: 26563462
pmcid: 4771416
doi: 10.1038/nrc4016
Kolvenbag, G. J., Blackledge, G. R. & Gotting-Smith, K. Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development. Prostate 34, 61–72 (1998).
pubmed: 9428389
doi: 10.1002/(SICI)1097-0045(19980101)34:1<61::AID-PROS8>3.0.CO;2-N
Tran, C. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324, 787–790 (2009).
pubmed: 19359544
pmcid: 19359544
doi: 10.1126/science.1168175
Penson, D. F. et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J. Clin. Oncol. 34, 2098–2106 (2016).
pubmed: 26811535
doi: 10.1200/JCO.2015.64.9285
Shore, N. D. et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 17, 153–163 (2016).
pubmed: 26774508
doi: 10.1016/S1470-2045(15)00518-5
Beer, T. M. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).
pubmed: 24881730
pmcid: 4418931
doi: 10.1056/NEJMoa1405095
Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).
pubmed: 22894553
doi: 10.1056/NEJMoa1207506
Hussain, M. et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N. Engl. J. Med. 378, 2465–2474 (2018).
pubmed: 29949494
doi: 10.1056/NEJMoa1800536
Smith, M. R. et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N. Engl. J. Med. 378, 1408–1418 (2018).
pubmed: 29420164
doi: 10.1056/NEJMoa1715546
pmcid: 29420164
Yoshida, T. et al. Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient. Cancer Res. 65, 9611–9616 (2005).
pubmed: 16266977
doi: 10.1158/0008-5472.CAN-05-0817
pmcid: 16266977
Balbas, M. D. et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife 2, e00499 (2013).
pubmed: 23580326
pmcid: 3622181
doi: 10.7554/eLife.00499
Joseph, J. D. et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 3, 1020–1029 (2013).
pubmed: 23779130
doi: 10.1158/2159-8290.CD-13-0226
pmcid: 23779130
Korpal, M. et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov. 3, 1030–1043 (2013).
pubmed: 23842682
doi: 10.1158/2159-8290.CD-13-0142
pmcid: 23842682
Visakorpi, T. et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat. Genet. 9, 401–406 (1995).
pubmed: 7795646
doi: 10.1038/ng0495-401
pmcid: 7795646
Sun, S. et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J. Clin. Investig. 120, 2715–2730 (2010).
pubmed: 20644256
doi: 10.1172/JCI41824
pmcid: 20644256
Arora, V. K. et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155, 1309–1322 (2013).
pubmed: 24315100
pmcid: 24315100
doi: 10.1016/j.cell.2013.11.012
Massie, C. E. et al. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J. 30, 2719–2733 (2011).
pubmed: 21602788
pmcid: 3155295
doi: 10.1038/emboj.2011.158
Eidelman, E., Twum-Ampofo, J., Ansari, J. & Siddiqui, M. M. The metabolic phenotype of prostate cancer. Front. Oncol. 7, 131 (2017).
pubmed: 28674679
pmcid: 5474672
doi: 10.3389/fonc.2017.00131
Zadra, G. & Loda, M. Metabolic vulnerabilities of prostate cancer: diagnostic and therapeutic opportunities. Cold Spring Harbor Perspect. Med. https://doi.org/10.1101/cshperspect.a030569 (2018).
Wu, X., Daniels, G., Lee, P. & Monaco, M. E. Lipid metabolism in prostate cancer. Am. J. Clin. Exp. Urol. 2, 111–120 (2014).
pubmed: 25374912
pmcid: 4219300
Pampaloni, F., Reynaud, E. G. & Stelzer, E. H. The third dimension bridges the gap between cell culture and live tissue. Nat. Rev. Mol. Cell Biol. 8, 839–845 (2007).
pubmed: 17684528
doi: 10.1038/nrm2236
pmcid: 17684528
Bovenga, F., Sabba, C. & Moschetta, A. Uncoupling nuclear receptor LXR and cholesterol metabolism in cancer. Cell Metab. 21, 517–526 (2015).
pubmed: 25863245
doi: 10.1016/j.cmet.2015.03.002
pmcid: 25863245
Nguyen, H. G. et al. Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model. Oncogene 33, 4521–4530 (2014).
pubmed: 24662833
pmcid: 4155805
doi: 10.1038/onc.2014.25
Barfeld, S. J. et al. c-Myc antagonises the transcriptional activity of the androgen receptor in prostate cancer affecting key gene networks. EBioMedicine 18, 83–93 (2017).
pubmed: 28412251
pmcid: 5405195
doi: 10.1016/j.ebiom.2017.04.006
Patel, R. et al. Sprouty2 loss-induced IL6 drives castration-resistant prostate cancer through scavenger receptor B1. EMBO Mol. Med. https://doi.org/10.15252/emmm.201708347 (2018).
Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 162, 454 (2015).
pubmed: 28843286
doi: 10.1016/j.cell.2015.06.053
pmcid: 28843286
Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).
pubmed: 20579941
pmcid: 3198787
doi: 10.1016/j.ccr.2010.05.026
Kim, W. H., Choi, C. H., Kang, S. K., Kwon, C. H. & Kim, Y. K. Ceramide induces non-apoptotic cell death in human glioma cells. Neurochem. Res. 30, 969–979 (2005).
pubmed: 16258846
doi: 10.1007/s11064-005-6223-y
pmcid: 16258846
Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432 (2019).
pubmed: 30686757
pmcid: 6430697
doi: 10.1016/j.chembiol.2018.11.016
Yang, W. S. et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl Acad. Sci. USA 113, E4966–E4975 (2016).
pubmed: 27506793
doi: 10.1073/pnas.1603244113
Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247–250 (2017).
pubmed: 29088702
pmcid: 5933935
doi: 10.1038/nature24297
Koljenovic, S. et al. Tissue characterization using high wave number Raman spectroscopy. J. Biomed. Opt. 10, 031116 (2005).
pubmed: 16229641
doi: 10.1117/1.1922307
Bluemn, E. G. et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell 32, 474–489 (2017).
pubmed: 29017058
pmcid: 29017058
doi: 10.1016/j.ccell.2017.09.003
Sharma, N. L. et al. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell 23, 35–47 (2013).
pubmed: 23260764
doi: 10.1016/j.ccr.2012.11.010
Hoefer, J. et al. Critical role of androgen receptor level in prostate cancer cell resistance to new generation antiandrogen enzalutamide. Oncotarget 7, 59781–59794 (2016).
pubmed: 27486973
pmcid: 5312348
doi: 10.18632/oncotarget.10926
Kregel, S. et al. Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer. Oncotarget 7, 26259–26274 (2016).
pubmed: 27036029
pmcid: 5041979
doi: 10.18632/oncotarget.8456
Li, J. et al. Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer. eLife https://doi.org/10.7554/eLife.20183 (2017).
Cui, Y. et al. Upregulation of glucose metabolism by NF-kappaB2/p52 mediates enzalutamide resistance in castration-resistant prostate cancer cells. Endocr. Relat. Cancer 21, 435–442 (2014).
pubmed: 24659479
pmcid: 4021715
doi: 10.1530/ERC-14-0107
Wang, L. et al. Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer. EBioMedicine 7, 50–61 (2016).
pubmed: 27322458
pmcid: 4909365
doi: 10.1016/j.ebiom.2016.03.022
Bader, D. A. et al. Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. Nat. Metab. 1, 70–85 (2019).
pubmed: 31198906
doi: 10.1038/s42255-018-0002-y
Rohrig, F. & Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16, 732–749 (2016).
pubmed: 27658529
doi: 10.1038/nrc.2016.89
pmcid: 27658529
Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13, 227–232 (2013).
pubmed: 23446547
pmcid: 3766957
doi: 10.1038/nrc3483
Shah, S. et al. Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism. Oncotarget 7, 43713–43730 (2016).
pubmed: 27248322
pmcid: 5190055
doi: 10.18632/oncotarget.9666
Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).
pubmed: 21576264
pmcid: 3093120
doi: 10.1101/gad.1987211
Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).
pubmed: 19693011
pmcid: 2931797
doi: 10.1038/nature08268
Camarda, R. et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat. Med. 22, 427–432 (2016).
pubmed: 26950360
pmcid: 4892846
doi: 10.1038/nm.4055
Samudio, I. et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J. Clin. Investig. 120, 142–156 (2010).
pubmed: 20038799
doi: 10.1172/JCI38942
Itkonen, H. M. et al. Lipid degradation promotes prostate cancer cell survival. Oncotarget 8, 38264–38275 (2017).
pubmed: 28415728
pmcid: 5503531
doi: 10.18632/oncotarget.16123
Schlaepfer, I. R. et al. Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol. Cancer Ther. 13, 2361–2371 (2014).
pubmed: 25122071
pmcid: 4185227
doi: 10.1158/1535-7163.MCT-14-0183
Flaig, T. W. et al. Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade. Oncotarget 8, 56051–56065 (2017).
pubmed: 28915573
pmcid: 5593544
doi: 10.18632/oncotarget.17359
Myers, J. S., von Lersner, A. K. & Sang, Q. X. Proteomic upregulation of fatty acid synthase and fatty acid binding protein 5 and identification of cancer- and race-specific pathway associations in human prostate cancer tissues. J. Cancer 7, 1452–1464 (2016).
pubmed: 27471561
pmcid: 4964129
doi: 10.7150/jca.15860
Khan, A. P. et al. Quantitative proteomic profiling of prostate cancer reveals a role for miR-128 in prostate cancer. Mol. Cell. Proteom. 9, 298–312 (2010).
doi: 10.1074/mcp.M900159-MCP200
Ursini-Siegel, J. et al. Elevated expression of DecR1 impairs ErbB2/Neu-induced mammary tumor development. Mol. Cell. Biol. 27, 6361–6371 (2007).
pubmed: 17636013
pmcid: 2099621
doi: 10.1128/MCB.00686-07
Miinalainen, I. J. et al. Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis. PLoS Genet. 5, e1000543 (2009).
pubmed: 19578400
pmcid: 2697383
doi: 10.1371/journal.pgen.1000543
Vriens, K. et al. Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity. Nature 566, 403–406 (2019).
pubmed: 30728499
pmcid: 6390935
doi: 10.1038/s41586-019-0904-1
Gilligan, M. M. et al. Aspirin-triggered proresolving mediators stimulate resolution in cancer. Proc. Natl Acad. Sci. USA 116, 6292–6297 (2019).
pubmed: 30862734
doi: 10.1073/pnas.1804000116
pmcid: 30862734
Volmer, R., van der Ploeg, K. & Ron, D. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc. Natl Acad. Sci. USA 110, 4628–4633 (2013).
pubmed: 23487760
doi: 10.1073/pnas.1217611110
pmcid: 23487760
Ho, N., Xu, C. & Thibault, G. From the unfolded protein response to metabolic diseases—lipids under the spotlight. J. Cell Sci. https://doi.org/10.1242/jcs.199307 (2018).
Naylor, D. J., Hoogenraad, N. J. & Hoj, P. B. Characterisation of several Hsp70 interacting proteins from mammalian organelles. Biochim. et. Biophys. Acta 1431, 443–450 (1999).
doi: 10.1016/S0167-4838(99)00070-9
Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007).
pubmed: 17703201
doi: 10.1038/nprot.2007.261
pmcid: 17703201
Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).
doi: 10.1038/nbt.1511
Cox, J. et al. Andromeda: a peptide search engine integrated into the MaxQuant environment. J. Proteome Res. 10, 1794–1805 (2011).
doi: 10.1021/pr101065j
UniProt, C. The Universal Protein Resource (UniProt) in 2010. Nucleic Acids Res. 38, D142–D148 (2010).
doi: 10.1093/nar/gkp846
Cox, J. et al. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol. Cell. Proteom. 13, 2513–2526 (2014).
doi: 10.1074/mcp.M113.031591
Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).
doi: 10.1038/nmeth.3901
Rath, N. et al. Rho kinase inhibition by AT13148 blocks pancreatic ductal adenocarcinoma invasion and tumor growth. Cancer Res. 78, 3321–3336 (2018).
pubmed: 29669760
pmcid: 6005347
Mackay, G. M., Zheng, L., van den Broek, N. J. & Gottlieb, E. Analysis of cell metabolism using LC-MS and isotope tracers. Methods Enzymol. 561, 171–196 (2015).
pubmed: 26358905
doi: 10.1016/bs.mie.2015.05.016
pmcid: 26358905
Tsugawa, H. et al. Comprehensive identification of sphingolipid species by in silico retention time and tandem mass spectral library. J. Cheminform. 9, 19 (2017).
pubmed: 28316657
pmcid: 5352698
doi: 10.1186/s13321-017-0205-3
Kind, T. et al. LipidBlast in silico tandem mass spectrometry database for lipid identification. Nat. Methods 10, 755–758 (2013).
pubmed: 23817071
pmcid: 3731409
doi: 10.1038/nmeth.2551
Hutchins, P. D., Russell, J. D. & Coon, J. J. LipiDex: an integrated software package for high-confidence lipid identification. Cell Syst. 6, 621–625 (2018).
pubmed: 29705063
pmcid: 5967991
doi: 10.1016/j.cels.2018.03.011
Christen, S. et al. Breast cancer-derived lung metastases show increased pyruvate carboxylase-dependent anaplerosis. Cell Rep. 17, 837–848 (2016).
pubmed: 27732858
doi: 10.1016/j.celrep.2016.09.042
Lorendeau, D. et al. Dual loss of succinate dehydrogenase (SDH) and complex I activity is necessary to recapitulate the metabolic phenotype of SDH mutant tumors. Metab. Eng. 43, 187–197 (2017).
pubmed: 27847310
doi: 10.1016/j.ymben.2016.11.005
van Gorsel, M., Elia, I. & Fendt, S. M. (13)C tracer analysis and metabolomics in 3D cultured cancer cells. Methods Mol. Biol. 1862, 53–66 (2019).
pubmed: 30315459
doi: 10.1007/978-1-4939-8769-6_4
Fernandez, C. A., Des Rosiers, C., Previs, S. F., David, F. & Brunengraber, H. Correction of 13C mass isotopomer distributions for natural stable isotope abundance. J. Mass Spectrom. 31, 255–262 (1996).
pubmed: 8799277
doi: 10.1002/(SICI)1096-9888(199603)31:3<255::AID-JMS290>3.0.CO;2-3
Kilkenny, C. et al. Animal research: reporting in vivo experiments-the ARRIVE guidelines. J. Cereb. Blood Flow. Metab. 31, 991–993 (2011).
pubmed: 21206507
pmcid: 3070981
doi: 10.1038/jcbfm.2010.220