Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cancer cells
Tóm tắt
Proxalutamide is a newly developed androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (PCa) that has entered phase III clinical trials. In the present study, we intended to elucidate the antitumor efficacy of proxalutamide through the metabolomic profiling of PCa cells. Two AR-positive PCa cell lines and two AR-negative PCa cell lines were investigated. Cell viability assays based on ATP quantitation were conducted. LC-Q/TOF-MS was used to analyze intracellular metabolites before or after the administration of proxalutamide and two other clinical AR antagonists (bicalutamide and enzalutamide). The results of this study showed that the inhibitory effect of proxalutamide on PCa cell proliferation was better than that of bicalutamide and enzalutamide, and proxalutamide preferentially affected AR-positive PCa cells over AR-negative cells. The metabolic composition of PCa cells changed significantly after proxalutamide administration, and these changes in response to proxalutamide were significantly different from those in the presence of the two other AR antagonists. In AR-positive cells, proxalutamide significantly decreased the intracellular levels of glutamine, glutamate, glutathione, cysteine, glycine, aspartate, uridine, cytidine and thymidine. However, the effects of the two other antagonists on these discriminant metabolites were ambiguous, and no changes in these metabolites were found in AR-negative cells. Our findings indicate that proxalutamide has inhibitory effects on glutamine metabolism, redox homeostasis and de novo pyrimidine synthesis in AR-positive PCa cells that enhance the cellular sensitivity to proxalutamide.
Tài liệu tham khảo
Romero-Otero J, Garcia-Gomez B, Duarte-Ojeda JM, Rodriguez-Antolin A, Vilaseca A, Carlsson SV, Touijer KA (2016) Active surveillance for prostate cancer. International journal of urology : official journal of the Japanese Urological Association 23(3):211–218. https://doi.org/10.1111/iju.13016
Poole A, Gill D, Hahn AW, Johnson E, Carroll E, Boucher K, Nussenzveig R, Maughan B, Agarwal N (2017) Incidence and characterization of Antiandrogen withdrawal syndrome after discontinuation of treatment with Enzalutamide in castration-resistant prostate Cancer. Clinical genitourinary cancer. https://doi.org/10.1016/j.clgc.2017.08.017
Bergerat JP, Ceraline J (2009) Pleiotropic functional properties of androgen receptor mutants in prostate cancer. Hum Mutat 30(2):145–157. https://doi.org/10.1002/humu.20848
Brooke GN, Bevan CL (2009) The role of androgen receptor mutations in prostate cancer progression. Current genomics 10(1):18–25. https://doi.org/10.2174/138920209787581307
Koochekpour S (2010) Androgen receptor signaling and mutations in prostate cancer. Asian journal of andrology 12(5):639–657. https://doi.org/10.1038/aja.2010.89
Abankwa D, Millard SM, Martel N, Choong CS, Yang M, Butler LM, Buchanan G, Tilley WD, Ueki N, Hayman MJ, Leong GM (2013) Ski-interacting protein (SKIP) interacts with androgen receptor in the nucleus and modulates androgen-dependent transcription. BMC Biochem 14:10. https://doi.org/10.1186/1471-2091-14-10
Mohler ML, Coss CC, Duke CB 3rd, Patil SA, Miller DD, Dalton JT (2012) Androgen receptor antagonists: a patent review (2008-2011). Expert opinion on therapeutic patents 22(5):541–565. https://doi.org/10.1517/13543776.2012.682571
Shafi AA, Yen AE, Weigel NL (2013) Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol Ther 140(3):223–238. https://doi.org/10.1016/j.pharmthera.2013.07.003
Culig Z (2017) Molecular mechanisms of Enzalutamide resistance in prostate Cancer. Curr Mol Biol Rep 3(4):230–235. https://doi.org/10.1007/s40610-017-0079-1
Guerrero J, Alfaro IE, Gomez F, Protter AA, Bernales S (2013) Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer. Prostate 73(12):1291–1305. https://doi.org/10.1002/pros.22674
Tong Y, Chen C, Wu J, Yang J, Zhang H, Wu X, Duan Y, Wei G, Qian W, Niu X (2014) Abstract 614: Proxalutamide (GT0918), a potent androgen receptor pathway inhibitor 74 (19 Supplement):614–614
Kelly RS, Vander Heiden MG, Giovannucci E, Mucci LA (2016) Metabolomic biomarkers of prostate Cancer: prediction, diagnosis, progression, prognosis, and recurrence. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 25(6):887–906. https://doi.org/10.1158/1055-9965.EPI-15-1223
Chen L, Cui H, Fang J, Deng H, Kuang P, Guo H, Wang X, Zhao L (2016) Glutamine deprivation plus BPTES alters etoposide- and cisplatin-induced apoptosis in triple negative breast cancer cells. Oncotarget 7(34):54691–54701. https://doi.org/10.18632/oncotarget.10579
Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJ, Lorkiewicz PK, Higashi RM, Fan TW, Dang CV (2012) Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 15(1):110–121. https://doi.org/10.1016/j.cmet.2011.12.009
Brown KK, Spinelli JB, Asara JM, Toker A (2017) Adaptive reprogramming of De novo pyrimidine synthesis is a metabolic vulnerability in triple-negative breast Cancer. Cancer Discov 7(4):391–399. https://doi.org/10.1158/2159-8290.CD-16-0611
Beloribi-Djefaflia S, Vasseur S, Guillaumond F (2016) Lipid metabolic reprogramming in cancer cells. Oncogenesis 5:e189. https://doi.org/10.1038/oncsis.2015.49
Fritz V, Benfodda Z, Henriquet C, Hure S, Cristol JP, Michel F, Carbonneau MA, Casas F, Fajas L (2013) Metabolic intervention on lipid synthesis converging pathways abrogates prostate cancer growth. Oncogene 32(42):5101–5110. https://doi.org/10.1038/onc.2012.523
Wondrak GT (2009) Redox-directed cancer therapeutics: molecular mechanisms and opportunities. Antioxid Redox Signal 11(12):3013–3069. https://doi.org/10.1089/ars.2009.2541
Tochhawng L, Deng S, Pervaiz S, Yap CT (2013) Redox regulation of cancer cell migration and invasion. Mitochondrion 13(3):246–253. https://doi.org/10.1016/j.mito.2012.08.002
Han YH, Kim SZ, Kim SH, Park WH (2008) Apoptosis in pyrogallol-treated Calu-6 cells is correlated with the changes of intracellular GSH levels rather than ROS levels. Lung Cancer 59(3):301–314. https://doi.org/10.1016/j.lungcan.2007.08.034
Wang W, Cai Q, Zhou F, Liu J, Jin X, Ni P, Lu M, Wang G, Zhang J (2018) Impaired pentose phosphate pathway in the development of 3D MCF-7 cells mediated intracellular redox disturbance and multi-cellular resistance without drug induction. Redox Biol 15:253–265. https://doi.org/10.1016/j.redox.2017.12.009
He J, Zhu Y, Aa J, Smith PF, De Ridder D, Wang G, Zheng Y (2017) Brain metabolic changes in rats following acoustic trauma. Front Neurosci 11:148. https://doi.org/10.3389/fnins.2017.00148
Martinez HD, Jasavala RJ, Izumi H, Fitzgerald LD, Trimmer JS, Hsing-Jien K, Wright ME (2008) RNA editing of androgen receptor gene transcripts in prostate cancer cells. J Biol Chem 283(44):29938–29949. https://doi.org/10.1074/jbc.M800534200
Tang L, Peng S, Bi Y, Shan P, Hu X (2014) A new method combining LDA and PLS for dimension reduction. PLoS One 9(5):e96944. https://doi.org/10.1371/journal.pone.0096944
Eagle H (1955) The specific amino acid requirements of a human carcinoma cell (stain HeLa) in tissue culture. J Exp Med 102(1):37–48. https://doi.org/10.1084/jem.102.1.37
Newsholme P, Procopio J, Lima MM, Pithon-Curi TC, Curi R (2003) Glutamine and glutamate--their central role in cell metabolism and function. Cell Biochem Funct 21(1):1–9. https://doi.org/10.1002/cbf.1003
Shanware NP, Mullen AR, DeBerardinis RJ, Abraham RT (2011) Glutamine: pleiotropic roles in tumor growth and stress resistance. J Mol Med 89(3):229–236. https://doi.org/10.1007/s00109-011-0731-9
van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, Ritchie W, Feng Y, Bailey CG, Deng N, Harvey K, Beith JM, Selinger CI, O'Toole SA, Rasko JE, Holst J (2016) ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene 35(24):3201–3208. https://doi.org/10.1038/onc.2015.381
Wasa M, Wang HS, Okada A (2002) Characterization of L-glutamine transport by a human neuroblastoma cell line. Am J Physiol Cell Physiol 282(6):C1246–C1253. https://doi.org/10.1152/ajpcell.00324.2001
White MA, Lin C, Rajapakshe K, Dong J, Shi Y, Tsouko E, Mukhopadhyay R, Jasso D, Dawood W, Coarfa C, Frigo DE (2017) Glutamine transporters are targets of multiple oncogenic signaling pathways in prostate Cancer. Molecular cancer research : MCR 15(8):1017–1028. https://doi.org/10.1158/1541-7786.MCR-16-0480
Zhang J, Mao S, Guo Y, Wu Y, Yao X, Huang Y (2019) Inhibition of GLS suppresses proliferation and promotes apoptosis in prostate cancer. Biosci Rep 39(6). https://doi.org/10.1042/BSR20181826
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) C-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239):762–765. https://doi.org/10.1038/nature07823
Wu Y, Guo T, Qiu Y, Lin Y, Yao Y, Lian W, Lin L, Song J, Yang H (2019) An inorganic prodrug, tellurium nanowires with enhanced ROS generation and GSH depletion for selective cancer therapy. Chem Sci 10(29):7068–7075. https://doi.org/10.1039/c9sc01070j
Kim J, Kim J, Bae JS (2016) ROS homeostasis and metabolism: a critical liaison for cancer therapy. Exp Mol Med 48(11):e269. https://doi.org/10.1038/emm.2016.119
Savarese DM, Savy G, Vahdat L, Wischmeyer PE, Corey B (2003) Prevention of chemotherapy and radiation toxicity with glutamine. Cancer Treat Rev 29(6):501–513. https://doi.org/10.1016/s0305-7372(03)00133-6
Sun C, Wang L, Xianyu B, Li T, Gao S, Xu H (2019) Selenoxide elimination manipulate the oxidative stress to improve the antitumor efficacy. Biomaterials 225:119514. https://doi.org/10.1016/j.biomaterials.2019.119514
Kim HJ, Yoon YM, Lee JH, Lee SH (2019) Protective role of Fucoidan on Cisplatin-mediated ER stress in renal proximal tubule epithelial cells. Anticancer Res 39(10):5515–5524. https://doi.org/10.21873/anticanres.13744
Harris IS, Brugge JS (2019) United they stand, divided they fall. Cell Metab 30(4):624–625. https://doi.org/10.1016/j.cmet.2019.09.008
McGregor GH, Campbell AD, Fey SK, Tumanov S, Sumpton D, Rodriguez Blanco G, Mackay G, Nixon C, Vazquez A, Sansom OJ, Kamphorst JJ (2019) Targeting the metabolic response to statin-mediated oxidative stress produces a synergistic anti-tumor response. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-19-0644
Sigoillot FD, Sigoillot SM, Guy HI (2004) Breakdown of the regulatory control of pyrimidine biosynthesis in human breast cancer cells. Int J Cancer 109(4):491–498. https://doi.org/10.1002/ijc.11717