Sprouty2 loss-induced IL6 drives castration-resistant prostate cancer through scavenger receptor B1.

Animals; Humans; Interleukin-6/metabolism; Intracellular Signaling Peptides and Proteins/genetics/metabolism; Male; Membrane Proteins/genetics/metabolism; Mice, Nude; Phenylenediamines/therapeutic use; Prostatic Neoplasms, Castration-Resistant/drug therapy/metabolism; Protein-Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Receptor, ErbB-2/genetics/metabolism; Receptors, Scavenger/metabolism; Scavenger Receptors, Class B/antagonists & inhibitors; Signal Transduction/drug effects/physiology; Sulfonamides/therapeutic use; androgen receptor; cholesterol; interleukin 6; prostate cancer; scavenger receptor B1

Abstract :

[en] Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of treatment-resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre-clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self-sufficient form of CRPC Mechanistically, HER2-IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1-mediated cholesterol uptake in SPRY2-deficient tumours. Systemically, IL6 elevated the levels of circulating cholesterol by inducing host adipose lipolysis and hepatic cholesterol biosynthesis. SPRY2-deficient CRPC is dependent on cholesterol bioavailability and SRB1-mediated tumoral cholesterol uptake for androgen biosynthesis. Importantly, treatment with ITX5061, a clinically safe SRB1 antagonist, decreased treatment resistance. Our results indicate that cholesterol transport blockade may be effective against SPRY2-deficient CRPC.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Patel, Rachana

Fleming, Janis

Mui, Ernest

Loveridge, Carolyn

Repiscak, Peter

Blomme, Arnaud ; Université de Liège - ULiège > Stem Cells-Cancer Signaling

Harle, Victoria

Salji, Mark

Ahmad, Imran

Teo, Katy

More authors (7 more)

Language :

English

Title :

Sprouty2 loss-induced IL6 drives castration-resistant prostate cancer through scavenger receptor B1.

Publication date :

2018

Journal title :

EMBO Molecular Medicine

ISSN :

1757-4676

eISSN :

1757-4684

Publisher :

Wiley-Blackwell, United Kingdom

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 09 June 2020

Statistics

Number of views

35 (0 by ULiège)

Number of downloads

35 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Ahmad I, Patel R, Singh LB, Nixon C, Seywright M, Barnetson RJ, Brunton VG, Muller WJ, Edwards J, Sansom OJ et al (2011) HER2 overcomes PTEN (loss)-induced senescence to cause aggressive prostate cancer. Proc Natl Acad Sci USA 108: 16392–16397
Ahmad I, Gao M, Patel R, Leung HY (2013) Modelling synergistic interactions between HER2, Sprouty2 and PTEN in driving prostate carcinogenesis. Asian J Androl 15: 323–327
Assinder SJ, Beniamen D, Lovicu FJ (2015) Cosuppression of Sprouty and Sprouty-related negative regulators of FGF signalling in prostate cancer: a working hypothesis. Biomed Res Int 2015: 827462
Bluemn EG, Coleman IM, Lucas JM, Coleman RT, Hernandez-Lopez S, Tharakan R, Bianchi-Frias D, Dumpit RF, Kaipainen A, Corella AN et al (2017) Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell 32: 474–489 e476
Cancer Genome Atlas Research N (2015) The molecular taxonomy of primary prostate cancer. Cell 163: 1011–1025
Chang KH, Li R, Kuri B, Lotan Y, Roehrborn CG, Liu J, Vessella R, Nelson PS, Kapur P, Guo X et al (2013) A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154: 1074–1084
Chun JY, Nadiminty N, Dutt S, Lou W, Yang JC, Kung HJ, Evans CP, Gao AC (2009) Interleukin-6 regulates androgen synthesis in prostate cancer cells. Clin Cancer Res 15: 4815–4822
Culig Z (2014) Proinflammatory cytokine interleukin-6 in prostate carcinogenesis. Am J Clin Exp Urol 2: 231–238
Del Puppoo M, Rauli S, Kienle MG (1995) Inhibition of cholesterol synthesis and hepatic 3-hydroxy-3-methylglutaryl-CoA reductase in rats by simvastatin and pravastatin. Lipids 30: 1057–1061
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
Divella R, De Luca R, Abbate I, Naglieri E, Daniele A (2016) Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation. J Cancer 7: 2346–2359
Doldi V, Callari M, Giannoni E, D'Aiuto F, Maffezzini M, Valdagni R, Chiarugi P, Gandellini P, Zaffaroni N (2015) Integrated gene and miRNA expression analysis of prostate cancer-associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation. Oncotarget 6: 31441–31460
Dorff TB, Goldman B, Pinski JK, Mack PC, Lara PN Jr, Van Veldhuizen PJ Jr, Quinn DI, Vogelzang NJ, Thompson IM Jr, Hussain MH (2010) Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clin Cancer Res 16: 3028–3034
Fearon KC, Glass DJ, Guttridge DC (2012) Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 16: 153–166
Fizazi K, De Bono JS, Flechon A, Heidenreich A, Voog E, Davis NB, Qi M, Bandekar R, Vermeulen JT, Cornfeld M et al (2012) Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer 48: 85–93
Flint TR, Janowitz T, Connell CM, Roberts EW, Denton AE, Coll AP, Jodrell DI, Fearon DT (2016) Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab 24: 672–684
Furuya Y, Sekine Y, Kato H, Miyazawa Y, Koike H, Suzuki K (2016) Low-density lipoprotein receptors play an important role in the inhibition of prostate cancer cell proliferation by statins. Prostate Int 4: 56–60
Gao M, Patel R, Ahmad I, Fleming J, Edwards J, McCracken S, Sahadevan K, Seywright M, Norman J, Sansom O et al (2012) SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis. EMBO Mol Med 4: 776–790
Hearn JW, AbuAli G, Reichard CA, Reddy CA, Magi-Galluzzi C, Chang KH, Carlson R, Rangel L, Reagan K, Davis BJ et al (2016) HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol 17: 1435–1444
Hu J, Zhang Z, Shen WJ, Azhar S (2010) Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metab 7: 47
James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ et al (2017) Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 377: 338–351
Kim O, Jiang T, Xie Y, Guo Z, Chen H, Qiu Y (2004) Synergism of cytoplasmic kinases in IL6-induced ligand-independent activation of androgen receptor in prostate cancer cells. Oncogene 23: 1838–1844
Kim JH, Cox ME, Wasan KM (2014) Effect of simvastatin on castration-resistant prostate cancer cells. Lipids Health Dis 13: 56
Leon CG, Locke JA, Adomat HH, Etinger SL, Twiddy AL, Neumann RD, Nelson CC, Guns ES, Wasan KM (2010) Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model. Prostate 70: 390–400
Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, Liu J, Upadhyay SK, Auchus RJ, Sharifi N (2015) Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 523: 347–351
Malinowska K, Neuwirt H, Cavarretta IT, Bektic J, Steiner H, Dietrich H, Moser PL, Fuchs D, Hobisch A, Culig Z (2009) Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer 16: 155–169
Mulholland DJ, Tran LM, Li Y, Cai H, Morim A, Wang S, Plaisier S, Garraway IP, Huang J, Graeber TG et al (2011) Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19: 792–804
Nagabhushan M, Miller CM, Pretlow TP, Giaconia JM, Edgehouse NL, Schwartz S, Kung HJ, de Vere White RW, Gumerlock PH, Resnick MI et al (1996) CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar. Can Res 56: 3042–3046
Patel R, Gao M, Ahmad I, Fleming J, Singh LB, Rai TS, McKie AB, Seywright M, Barnetson RJ, Edwards J et al (2013) Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression. J Clin Invest 123: 1157–1175
Pencik J, Schlederer M, Gruber W, Unger C, Walker SM, Chalaris A, Marie IJ, Hassler MR, Javaheri T, Aksoy O et al (2015) STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nat Commun 6: 7736
Rice KR, Koch MO, Cheng L, Masterson TA (2012) Dyslipidemia, statins and prostate cancer. Expert Rev Anticancer Ther 12: 981–990
Rick FG, Schally AV, Szalontay L, Block NL, Szepeshazi K, Nadji M, Zarandi M, Hohla F, Buchholz S, Seitz S (2012) Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases. Proc Natl Acad Sci USA 109: 1655–1660
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G et al (2015) Integrative clinical genomics of advanced prostate cancer. Cell 161: 1215–1228
Rossi JF, Lu ZY, Jourdan M, Klein B (2015) Interleukin-6 as a therapeutic target. Clin Cancer Res 21: 1248–1257
Roychowdhury S, Chinnaiyan AM (2016) Translating cancer genomes and transcriptomes for precision oncology. CA Cancer J Clin 66: 75–88
Sartor O, Pal SK (2013) Abiraterone and its place in the treatment of metastatic CRPC. Nat Rev Clin Oncol 10: 6–8
Schorghofer D, Kinslechner K, Preitschopf A, Schutz B, Rohrl C, Hengstschlager M, Stangl H, Mikula M (2015) The HDL receptor SR-BI is associated with human prostate cancer progression and plays a possible role in establishing androgen independence. Reprod Biol Endocrinol 13: 88
Schutzman JL, Martin GR (2012) Sprouty genes function in suppression of prostate tumorigenesis. Proc Natl Acad Sci USA 109: 20023–20028
Shiota M, Bishop JL, Takeuchi A, Nip KM, Cordonnier T, Beraldi E, Kuruma H, Gleave ME, Zoubeidi A (2015) Inhibition of the HER2-YB1-AR axis with Lapatinib synergistically enhances Enzalutamide anti-tumor efficacy in castration resistant prostate cancer. Oncotarget 6: 9086–9098
Siegall CB, Schwab G, Nordan RP, FitzGerald DJ, Pastan I (1990) Expression of the interleukin 6 receptor and interleukin 6 in prostate carcinoma cells. Can Res 50: 7786–7788
Sramkoski RM, Pretlow TG II, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, Marengo SR, Rhim JS, Zhang D, Jacobberger JW (1999) A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim 35: 403–409
Sridhar SS, Hotte SJ, Chin JL, Hudes GR, Gregg R, Trachtenberg J, Wang L, Tran-Thanh D, Pham NA, Tsao MS et al (2010) A multicenter phase II clinical trial of lapatinib (GW572016) in hormonally untreated advanced prostate cancer. Am J Clin Oncol 33: 609–613
Syder AJ, Lee H, Zeisel MB, Grove J, Soulier E, Macdonald J, Chow S, Chang J, Baumert TF, McKeating JA et al (2011) Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors. J Hepatol 54: 48–55
Tansey JT, Sztalryd C, Hlavin EM, Kimmel AR, Londos C (2004) The central role of perilipin a in lipid metabolism and adipocyte lipolysis. IUBMB Life 56: 379–385
Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B et al (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell 18: 11–22
Tepper CG, Boucher DL, Ryan PE, Ma AH, Xia L, Lee LF, Pretlow TG, Kung HJ (2002) Characterization of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line. Can Res 62: 6606–6614
Twiddy AL, Cox ME, Wasan KM (2012) Knockdown of scavenger receptor class B type I reduces prostate specific antigen secretion and viability of prostate cancer cells. Prostate 72: 955–965
Wang H, Cui XX, Goodin S, Ding N, Van Doren J, Du Z, Huang MT, Liu Y, Cheng X, Dipaola RS et al (2014) Inhibition of IL-6 expression in LNCaP prostate cancer cells by a combination of atorvastatin and celecoxib. Oncol Rep 31: 835–841
Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, Kim K, Sawyers CL (2010) Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci USA 107: 16759–16765
Watson PA, Arora VK, Sawyers CL (2015) Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer 15: 701–711
Whang YE, Armstrong AJ, Rathmell WK, Godley PA, Kim WY, Pruthi RS, Wallen EM, Crane JM, Moore DT, Grigson G et al (2013) A phase II study of lapatinib, a dual EGFR and HER-2 tyrosine kinase inhibitor, in patients with castration-resistant prostate cancer. Urol Oncol 31: 82–86
Yang Y, Bai Y, He Y, Zhao Y, Chen J, Ma L, Pan Y, Hinten M, Zhang J, Karnes RJ et al (2018) PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer. Clin Cancer Res 24: 834–846
Yap TA, Smith AD, Ferraldeschi R, Al-Lazikani B, Workman P, de Bono JS (2016) Drug discovery in advanced prostate cancer: translating biology into therapy. Nat Rev Drug Discovery 15: 699–718
Yu O, Eberg M, Benayoun S, Aprikian A, Batist G, Suissa S, Azoulay L (2014) Use of statins and the risk of death in patients with prostate cancer. J Clin Oncol 32: 5–11
Yu SH, Zheng Q, Esopi D, Macgregor-Das A, Luo J, Antonarakis ES, Drake CG, Vessella R, Morrissey C, De Marzo AM et al (2015) A paracrine role for IL6 in prostate cancer patients: lack of production by primary or metastatic tumor cells. Cancer Immunol Res 3: 1175–1184
Zhai W, Xu C, Ling Y, Liu S, Deng J, Qi Y, Londos C, Xu G (2010) Increased lipolysis in adipose tissues is associated with elevation of systemic free fatty acids and insulin resistance in perilipin null mice. Horm Metab Res 42: 247–253
Zhao L, Chen Y, Tang R, Chen Y, Li Q, Gong J, Huang A, Varghese Z, Moorhead JF, Ruan XZ (2011) Inflammatory stress exacerbates hepatic cholesterol accumulation via increasing cholesterol uptake and de novo synthesis. J Gastroenterol Hepatol 26: 875–883