New inhibitor targeting Acyl-CoA synthetase 4 reduces breast and prostate tumor growth, therapeutic resistance and steroidogenesis

Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN. A cancer. J Clin 68:394–424. https://doi.org/10.3322/caac.21492 Perou CM, Sørile T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752. https://doi.org/10.1038/35021093 Sorlie T, Sørlie T, Perou CM et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874. https://doi.org/10.1073/pnas.191367098 Sartor O, de Bono JS, de Bono SJ (2018) Metastatic prostate cancer. N Engl J Med 378:645–657. https://doi.org/10.1056/NEJMra1701695 Mashek DG, Bornfeldt KE, Coleman RA et al (2004) Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family. J Lipid Res 45:1958–1961. https://doi.org/10.1194/jlr.E400002-JLR200 Maloberti PM, Duarte AB, Orlando UD et al (2010) Functional interaction between acyl-coa synthetase 4, lipoxygenases and cyclooxygenase-2 in the aggressive phenotype of breast cancer cells. PLoS ONE 5:1–12. https://doi.org/10.1371/journal.pone.0015540 Wu X, Deng F, Li Y, et al (2015) ACSL4 promotes prostate cancer growth, invasion and hormonal resistance. Oncotarget 6:44849–44863. https://doi.org/10.18632/oncotarget.6438 Sung YK, Hwang SY, Park MK et al (2003) Fatty acid-CoA ligase 4 is overexpressed in human hepatocellular carcino. Cancer Sci 94:421–424. https://doi.org/10.1111/j.1349-7006.2003.tb01458.x Cao Y, Dave KB, Doan TP, Prescott SM (2001) Fatty acid CoA ligase 4 is up-regulated in colon adenocarcinoma. Cancer Res 61:8429–8434 Orlando UD, Garona J, Ripoll GV et al (2012) The functional interaction between acyl-coa synthetase 4, 5-lipooxygenase and cyclooxygenase-2 controls tumor growth: a novel therapeutic target. PLoS ONE 7:1–14. https://doi.org/10.1371/journal.pone.0040794 Monaco ME, Creighton CJ, Lee P et al (2010) Expression of long-chain fatty acyl-coa synthetase 4 in breast and prostate cancers is associated with sex steroid hormone receptor negativity. Transl Oncol 3:91–98. https://doi.org/10.1593/tlo.09202 Orlando UD, Castillo AF, Dattilo MA, et al (2015) Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer. Oncotarget 6:42632–42650. https://doi.org/10.18632/oncotarget.5822 Wu X, Li Y, Wang J et al (2013) Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer. PLoS ONE 8:1–20. https://doi.org/10.1371/journal.pone.0077060 Orlando UD, Castillo AF, Medrano MAR et al (2019) Acyl-CoA synthetase-4 is implicated in drug resistance in breast cancer cell lines involving the regulation of energy-dependent transporter expression. Biochem Pharmacol 159:52–63. https://doi.org/10.1016/J.BCP.2018.11.005 Castillo AF, Orlando UD, Lopez P et al (2016) Gene expression profile and signaling pathways in MCF-7 breast cancer cells mediated by acyl-coa synthetase 4 overexpression. Transcr Open Access 3:1–9. https://doi.org/10.4172/2329-8936.1000120 Kang MJ, Fujino T, Sasano H, et al (1997) A novel arachidonate-preferring acyl-CoA synthetase is present in steroidogenic cells of the rat adrenal, ovary, and testis. Proc Natl Acad Sci USA 94:2880–2884. https://doi.org/10.1073/pnas.94.7.2880 Cornejo Maciel F, Maloberti P, Neuman I et al (2005) An arachidonic acid-preferring acyl-CoA synthetase is a hormone-dependent and obligatory protein in the signal transduction pathway of steroidogenic hormones. J Mol Endocrinol 34:655–666. https://doi.org/10.1677/jme.1.01691 Maloberti P, Castilla R, Castillo F et al (2005) Silencing the expression of mitochondrial acyl-CoA thioesterase I and acyl-CoA synthetase 4 inhibits hormone-induced steroidogenesis. FEBS J 272:1804–1814. https://doi.org/10.1111/j.1742-4658.2005.04616.x Paz C, Cornejo Maciel F, Gorostizaga A et al (2016) Role of protein phosphorylation and tyrosine phosphatases in the adrenal regulation of steroid synthesis and mitochondrial function. Front Endocrinol 7:1–15. https://doi.org/10.3389/fendo.2016.00060 Privalle CT, Crivello JF, Jefcoate CR (1983) Regulation of intramitochondrial cholesterol transfer to side-chain cleavage cytochrome P-450 in rat adrenal gland. Proc Natl Acad Sci USA 80:702–706. https://doi.org/10.1073/pnas.80.3.702 Capper CP, Rae JM, Auchus RJ (2016) The metabolism, analysis, and targeting of steroid hormones in breast and prostate cancer. Horm Cancer 7:149–164. https://doi.org/10.1007/s12672-016-0259-0 Courtin A, Smyth T, Hearn K et al (2016) Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib. Br J Cancer 115:1069–1077. https://doi.org/10.1038/bjc.2016.294 Yamaguchi N, Lucena-Araujo AR, Nakayama S et al (2014) Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer. Lung Cancer 83:37–43. https://doi.org/10.1016/j.lungcan.2013.09.019 Sudhan DR, Guerrero-Zotano A, Won H et al (2020) Hyperactivation of Torc1 drives resistance to the pan-her tyrosine kinase inhibitor neratinib in Her2-mutant cancers. Cancer Cell 37(2):258–259. https://doi.org/10.1016/j.ccell.2020.01.010 Colombero C, Papademetrio D, Sacca P et al (2017) Role of 20-hydroxyeicosatetraenoic acid (20-HETE) in androgen-mediated cell viability in prostate cancer cells. Horm Cancer 8:243–256. https://doi.org/10.1007/s12672-017-0299-0 Ascoli M (1981) Regulation of gonadotropin receptors and gonadotropin responses in a clonal strain of Leydig tumor cells by epidermal growth factor. J Biol Chem 256:179–183 Rae PA, Gutmann NS, Tsao J, Schimmer BP (2006) Mutations in cyclic AMP-dependent protein kinase and corticotropin (ACTH)-sensitive adenylate cyclase affect adrenal steroidogenesis. Proc Natl Acad Sci 76:1896–1900. https://doi.org/10.1073/pnas.76.4.1896 Kim JH, Lewin TM, Coleman RA (2001) Expression and characterization of recombinant rat acyl-CoA synthetases 1, 4, and 5: selective inhibition by triacsin C and thiazolidinediones. J Biol Chem 276:24667–24673. https://doi.org/10.1074/jbc.M010793200 Castillo AF, Cornejo Maciel F, Castilla R et al (2006) cAMP increases mitochondrial cholesterol transport through the induction of arachidonic acid release inside this organelle in Leydig cells. FEBS J 273:5011–5021. https://doi.org/10.1111/j.1742-4658.2006.05496.x Chasalow F, Marr H, Haour F, Saez JM (1979) Testicular steroidogenesis after human chorionic gonadotropin desensitization in rats. J Biol Chem 256:5613–5617 Mele PG, Dada LA, Paz C et al (1996) Site of action of proteinases in the activation of steroidogenesis in rat adrenal gland. Biochim Biophys Acta 1310:260–268. https://doi.org/10.1016/0167-4889(95)00177-8 Yamamoto A, Kiguchi N, Kobayashi Y et al (2011) Pharmacological relationship between nicotinic and opioid systems in analgesia and corticosterone elevation. Life Sci 89:956–961. https://doi.org/10.1016/j.lfs.2011.10.004 Orellana-Serradell O, Poblete CE, Sanchez C et al (2015) Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep 33:1599–1608. https://doi.org/10.3892/or.2015.3746 Perera Y, Farina HG, Hernández I et al (2008) Systemic administration of a peptide that impairs the Protein Kinase (CK2) phosphorylation reduces solid tumor growth in mice. Int J Cancer 122:57–62. https://doi.org/10.1002/ijc.23013 Ripoll GV, Giron S, Krzymuski MJ et al (2008) Antitumor effects of desmopressin in combination with chemotherapeutic agents in a mouse model of breast cancer. Anticancer Res 25:2607–2611 Ortega HH, Salvetti NR, Padmanabhan V (2009) Developmental programming: prenatal androgen excess disrupts ovarian steroid receptor balance. Reproduction 135:865–877. https://doi.org/10.1530/REP-08-0491 Ciriello G, Gatza ML, Beck AH et al (2015) Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163:506–519. https://doi.org/10.1016/j.cell.2015.09.033 Long Q, Xu J, Osunkoya AO et al (2014) Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence. Cancer Res 74:3228–3237. https://doi.org/10.1158/0008-5472.CAN-13-2699 Hisanaga Y, Ago H, Nakagawa N et al (2004) Structural basis of the substrate-specific two-step catalysis of long chain fatty acyl-CoA synthetase dimer. J Biol Chem 279:31717–31726. https://doi.org/10.1074/jbc.M400100200 Askari B, Kanter JE, Sherrid AM et al (2007) Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a peroxisome proliferator-activated receptor-gamma-independent mechanism in human arterial smooth muscle cells and macrophages. Diabetes 56:1143–1152. https://doi.org/10.2337/db06-0267 Yan S, Yang XF, Liu HL et al (2015) Long-chain acyl-CoA synthetase in fatty acid metabolism involved in liver and other diseases: an update. World J Gastroenterol 12:3492–3498. https://doi.org/10.3748/wjg.v21.i12.3492 Coleman RA, Lewin TM, Van Horn CG, Gonzalez-Baró MR (2002) Do long-chain Acyl-CoA synthetases regulate fatty acid entry into synthetic versus degradative pathways? J Nutr 132:2123–2126. https://doi.org/10.1093/jn/132.8.2123 Kang MJ, Fujino T, Sasano H et al (1997) A novel arachidonate-preferring acyl-CoA synthetase is present in steroidogenic cells of the rat adrenal, ovary, and testis. Proc Natl Acad Sci USA 94:2880–2884. https://doi.org/10.1073/pnas.94.7.2880 Mashek DG, Li LO, Coleman RA (2006) Rat long-chain acyl-CoA synthetase mRNA, protein, and activity vary in tissue distribution and in response to diet. J Lipid Res 47:2004–2010. https://doi.org/10.1194/jlr.M600150-JLR200 Li LO, Klett EL, Coleman RA (2010) Acyl-CoA synthesis, lipid metabolism and lipotoxicity. Biochim Biophys Acta Mol Cell Biol Lipids 1801:246–251. https://doi.org/10.1016/j.bbalip.2009.09.024 Klett EL, Chen S, Yechoor A et al (2017) Long-chain acyl-CoA synthetase isoforms differ in preferences for eicosanoid species and long-chain fatty acids. J Lipid Res 58:884–894. https://doi.org/10.1194/jlr.M072512 Cooke M, Orlando U, Maloberti P et al (2011) Tyrosine phosphatase SHP2 regulates the expression of acyl-CoA synthetase ACSL4. J Lipid Res 52:1936–1948. https://doi.org/10.1194/jlr.M015552 Pham S, Deb S, Ming DS et al (2014) Next-generation steroidogenesis inhibitors, dutasteride and abiraterone, attenuate but still do not eliminate androgen biosynthesis in 22RV1 cells in vitro. J Steroid Biochem Mol Biol 144:436–444. https://doi.org/10.1016/j.jsbmb.2014.09.004 Vessey DA, Kelley M, Warren RS (2004) Characterization of triacsin C inhibition of short-, medium-, and long-chain fatty acid: CoA ligases of human liver. J Biochem Mol Toxicol 18:100–106. https://doi.org/10.1002/jbt.20009 Maloberti P, Lozano RC, Mele PG et al (2002) Concerted regulation of free arachidonic acid and hormone-induced steroid synthesis by acyl-CoA thioesterases and acyl-CoA synthetases in adrenal cells. Eur J Biochem 269:5599–5607. https://doi.org/10.1046/j.1432-1033.2002.03267.x Dechandt CRP, Zuccolotto-dos-Reis FH, Teodoro BG et al (2017) Triacsin C reduces lipid droplet formation and induces mitochondrial biogenesis in primary rat hepatocytes. J Bioenerg Biomembr 49:399–411. https://doi.org/10.1007/s10863-017-9725-9 Schönfeld P, Wieckowski MR, Wojtczak L (2000) Long-chain fatty acid-promoted swelling of mitochondria: Further evidence for the protonophoric effect of fatty acids in the inner mitochondrial membrane. FEBS Lett 471:108–112. https://doi.org/10.1016/S0014-5793(00)01376-4 Hirshfield IN, Koritz SB (1964) The stimulation of pregnenolone synthesis in the large particles from rat adrenals by some agents which cause mitochondrial swelling. Biochemistry 3:1994–1998. https://doi.org/10.1021/bi00900a036 Belosludtsev K, Belosludtseva N, Agafonov A et al (2014) Ca2 +-dependent permeabilization of mitochondria and liposomes by palmitic and oleic acids: a comparative study. Biochim Biophys Acta Biomembr 1838:2600–2606. https://doi.org/10.1016/j.bbamem.2014.06.017 Gordon JA, Noble JW, Midha A et al (2019) Upregulation of scavenger receptor B1 is required for steroidogenic and nonsteroidogenic cholesterol metabolism in prostate cancer. Cancer Res 79:3320–3331. https://doi.org/10.1158/0008-5472.CAN-18-2529 Clark BJ, Wells J, King SR, Stocco DM (1994) The purification, cloning, and expression of a novel luteinizing hormone- induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 269:28314–28322 Stocco DM (2001) StAR protein and the regulation of steroid hormone biosynthesis. Annu Rev Physiol 63:193–213. https://doi.org/10.1146/annurev.physiol.63.1.193 Jiang X, Guo S, Zhang Y et al (2020) LncRNA NEAT1 promotes docetaxel resistance in prostate cancer by regulating ACSL4 via sponging miR-34a-5p and miR-204–5p. Cell Signal 65:109422. https://doi.org/10.1016/j.cellsig.2019.109422 Sydes MR, Spears MR, Mason MD et al (2018) Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol 29:1235–1248. https://doi.org/10.1093/annonc/mdy072 Neophytou C, Boutsikos P, Papageorgis P (2018) Molecular mechanisms and emerging therapeutic targets of triple-negative breast cancer metastasis. Front Oncol 8:1–13. https://doi.org/10.3389/fonc.2018.00031 Sebastiano MR, Konstantinidou G (2019) Targeting long chain acyl-coa synthetases for cancer therapy. Int J Mol Sci 15:1–16. https://doi.org/10.3390/ijms20153624 Sánchez-Martínez R, Cruz-Gil S, de Cedrón MG, et al (2015) A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy. Oncotarget 36:38719–38736. https://doi.org/10.18632/oncotarget.5340 Miller WL (2007) Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim Biophys Acta Mol Cell Biol Lipids 1771:663–676. https://doi.org/10.1016/j.bbalip.2007.02.012 Miller WL, Auchus RJ (2011) The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 32:81–151. https://doi.org/10.1210/er.2010-0013 Dillard PR, Lin MF, Khan SA (2008) Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Mol Cell Endocrinol 295:115–120. https://doi.org/10.1016/j.mce.2008.08.013 Ko Y, Balk S (2005) Targeting steroid hormone receptor pathways in the treatment of hormone dependent cancers. Curr Pharm Biotechnol 5:459–470. https://doi.org/10.2174/1389201043376616 Kazi A, Xiang S, Yang H et al (2019) Dual farnesyl and geranyl transferase inhibitor thwarts mutant KRAS-driven patient-derived pancreatic tumors. Clin Cancer Res 25:5984–5996. https://doi.org/10.1158/1078-0432.CCR-18-3399 Armando RG, Gomez DM, Gomez DE (2016) AZT exerts its antitumoral effect by telomeric and non-telomeric effects in a mammary adenocarcinoma model. Oncol Rep 36:2731–2736. https://doi.org/10.3892/or.2016.5094 Watson PA, Arora VK, Sawyers CL (2015) Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer 15:701–711. https://doi.org/10.1038/nrc4016