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World Journal of Urology

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01-05-2016 | Original Article

Inhibition of IGF-1R diminishes transcriptional activity of the androgen receptor and its constitutively active, C-terminally truncated counterparts Q640X and AR-V7

Authors: Friedemann Zengerling, Anca Azoitei, Alexander Herweg, Florian Jentzmik, Marcus V. Cronauer

Published in: World Journal of Urology | Issue 5/2016

Abstract

Purpose

Failure of endocrine treatment in castration-resistant prostate cancer (CRPC) is often associated with the emergence of C-terminally truncated androgen receptor variants that function as constitutively active transcription factors (i.e., AR∆LBD). The mechanisms involved in the regulation of AR∆LBD signaling are largely unknown. Since the IGF-1 pathway was repeatedly shown to affect AR function, we studied whether an inhibition of IGF-1R could also affect AR∆LBD signaling.

Methods

Regulation of androgen receptor (AR) and AR∆LBD signaling was analyzed by reporter gene assays, immunoblotting, ELISA and quantitative RT-PCR.

Results

Inhibition of IGF-1R with the small-molecule inhibitor NVP-AEW541 reduced the transcriptional activity of the AR and its truncated counterparts Q640X and AR-V7. As shown in Q640X, the inhibition of transcriptional activity was paralleled by a decreased receptor phosphorylation.

Conclusions

Inhibition of IGF-1R leads to a down-regulation of AR∆LBD signaling and provides a rationale for CRPC therapies targeting growth factor receptors.

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Knudsen KE, Penning TM (2010) Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab 21:315–324. doi:10.1016/j.tem.2010.01.002 CrossRefPubMedPubMedCentral

Ware KE, Garcia-Blanco MA, Armstrong AJ, Dehm SM (2014) Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer. EndocrRelat Cancer 21:T87–t103. doi:10.1530/erc-13-0470 CrossRef

Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, Nelson PS, Montgomery RB (2011) Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 17:5913–5925. doi:10.1158/1078-0432.ccr-11-0728 CrossRefPubMedPubMedCentral

Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM (2013) Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 73:483–489. doi:10.1158/0008-5472.can-12-3630 CrossRefPubMedPubMedCentral

Culig Z, Hobisch A, Cronauer MV, Radmayr C, Trapman J, Hittmair A, Bartsch G, Klocker H (1994) Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 54:5474–5478PubMed

Nickerson T, Chang F, Lorimer D, Smeekens SP, Sawyers CL, Pollak M (2001) In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgen independence is associated with increased expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR). Cancer Res 61:6276–6280PubMed

Pandini G, Mineo R, Frasca F, Roberts CT Jr, Marcelli M, Vigneri R, Belfiore A (2005) Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells. Cancer Res 65:1849–1857. doi:10.1158/0008-5472.can-04-1837 CrossRefPubMed

Turney BW, Turner GD, Brewster SF, Macaulay VM (2011) Serial analysis of resected prostate cancer suggests up-regulation of type 1 IGF receptor with disease progression. BJU Int 107:1488–1499. doi:10.1111/j.1464-410X.2010.09556.x CrossRefPubMed

Liu X, Choi RY, Jawad SM, Arnold JT (2011) Androgen-induced PSA expression requires not only activation of AR but also endogenous IGF-I or IGF-I/PI3K/Akt signaling in human prostate cancer epithelial cells. Prostate 71:766–777. doi:10.1002/pros.21293 CrossRefPubMedPubMedCentral

10.

Lapouge G, Marcias G, Erdmann E, Kessler P, Cruchant M, Serra S, Bergerat JP, Ceraline J (2008) Specific properties of a C-terminal truncated androgen receptor detected in hormone refractory prostate cancer. Adv Exp Med Biol 617:529–534. doi:10.1007/978-0-387-69080-3_53 CrossRefPubMed

11.

Zengerling F, Streicher W, Schrader AJ, Schrader M, Nitzsche B, Cronauer MV, Hopfner M (2012) Effects of sorafenib on C-terminally truncated androgen receptor variants in human prostate cancer cells. Int J Mol Sci 13:11530–11542. doi:10.3390/ijms130911530 CrossRefPubMedPubMedCentral

12.

Ceraline J, Cruchant MD, Erdmann E, Erbs P, Kurtz JE, Duclos B, Jacqmin D, Chopin D, Bergerat JP (2004) Constitutive activation of the androgen receptor by a point mutation in the hinge region: a new mechanism for androgen-independent growth in prostate cancer. Int J Cancer 108:152–157. doi:10.1002/ijc.11404 CrossRefPubMed

13.

Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ (2008) Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res 68:5469–5477. doi:10.1158/0008-5472.can-08-0594 CrossRefPubMedPubMedCentral

14.

Streicher W, Luedeke M, Azoitei A, Zengerling F, Herweg A, Genze F, Schrader MG, Schrader AJ, Cronauer MV (2014) Stilbene induced inhibition of androgen receptor dimerization: implications for AR and ARDeltaLBD-signalling in human prostate cancer cells. PLoS ONE 9(6):e98566. doi:10.1371/journal.pone.0098566 CrossRefPubMedPubMedCentral

15.

Streicher W, Zengerling F, Laschak M, Weidemann W, Hopfner M, Schrader AJ, Jentzmik F, Schrader M, Cronauer MV (2012) AR-Q640X, a model to study the effects of constitutively active C-terminally truncated AR variants in prostate cancer cells. World J Urol 30:333–339. doi:10.1007/s00345-012-0842-0 CrossRefPubMed

16.

Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM, Sun H, Nelson PS, Plymate SR (2010) Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 120:2715–2730. doi:10.1172/jci41824 CrossRefPubMedPubMedCentral

17.

Pietrzkowski Z, Mulholland G, Gomella L, Jameson BA, Wernicke D, Baserga R (1993) Inhibition of growth of prostatic cancer cell lines by peptide analogues of insulin-like growth factor 1. Cancer Res 53:1102–1106PubMed

18.

Shukla S, Mishra A, Fu P, MacLennan GT, Resnick MI, Gupta S (2005) Up-regulation of insulin-like growth factor binding protein-3 by apigenin leads to growth inhibition and apoptosis of 22Rv1 xenograft in athymic nude mice. FASEB J 19:2042–2044. doi:10.1096/fj.05-3740fje PubMed

19.

Gioeli D, Paschal BM (2012) Post-translational modification of the androgen receptor. Mol Cell Endocrinol 352:70–78. doi:10.1016/j.mce.2011.07.004 CrossRefPubMed

20.

Chen S, Gulla S, Cai C, Balk SP (2012) Androgen receptor serine 81 phosphorylation mediates chromatin binding and transcriptional activation. J Biol Chem 287:8571–8583. doi:10.1074/jbc.M111.325290 CrossRefPubMedPubMedCentral

21.

Wu JD, Haugk K, Woodke L, Nelson P, Coleman I, Plymate SR (2006) Interaction of IGF signaling and the androgen receptor in prostate cancer progression. J Cell Biochem 99:392–401. doi:10.1002/jcb.20929 CrossRefPubMed

22.

Qu Y, Dai B, Ye D, Kong Y, Chang K, Jia Z, Yang X, Zhang H, Zhu Y, Shi G (2015) Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep 5:7654. doi:10.1038/srep07654 CrossRefPubMedPubMedCentral

23.

Iwamura M, Sluss PM, Casamento JB, Cockett AT (1993) Insulin-like growth factor I: action and receptor characterization in human prostate cancer cell lines. Prostate 22:243–252CrossRefPubMed

24.

Philippou A, Armakolas A, Koutsilieris M (2013) Evidence for the possible biological significance of the igf-1 gene alternative splicing in prostate cancer. Front Endocrinol (Lausanne) 4:31. doi:10.3389/fendo.2013.00031

25.

Sun F, Chen HG, Li W, Yang X, Wang X, Jiang R, Guo Z, Chen H, Huang J, Borowsky AD, Qiu Y (2014) Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J Biol Chem 289:1529–1539. doi:10.1074/jbc.M113.492140 CrossRefPubMedPubMedCentral

26.

Kesler CT, Gioeli D, Conaway MR, Weber MJ, Paschal BM (2007) Subcellular localization modulates activation function 1 domain phosphorylation in the androgen receptor. Mol Endocrinol 21:2071–2084. doi:10.1210/me.2007-0240 CrossRefPubMed

27.

Koryakina Y, Ta HQ, Gioeli D (2014) Androgen receptor phosphorylation: biological context and functional consequences. Endocr Relat Cancer 21:T131–T145. doi:10.1530/erc-13-0472 CrossRefPubMedPubMedCentral

28.

Loughran G, Huigsloot M, Kiely PA, Smith LM, Floyd S, Ayllon V, O’Connor R (2005) Gene expression profiles in cells transformed by overexpression of the IGF-I receptor. Oncogene 24:6185–6193. doi:10.1038/sj.onc.1208772 CrossRefPubMed

29.

Liu R, Tian B, Gearing M, Hunter S, Ye K, Mao Z (2008) Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion. Proc Natl Acad Sci USA 105:7570–7575. doi:10.1073/pnas.0712306105 CrossRefPubMedPubMedCentral

30.

Kato H, Sekine Y, Furuya Y, Miyazawa Y, Koike H, Suzuki K (2015) Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor. Biochem Biophys Res Commun. doi:10.1016/j.bbrc.2015.03.178

31.

Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bartschi D, Pollak M, Lui L, Endt K, Schiess R, Ruschoff JH, Cathomas R, Gillessen S (2014) Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol 66:468–474. doi:10.1016/j.eururo.2013.12.057 CrossRefPubMed

Title: Inhibition of IGF-1R diminishes transcriptional activity of the androgen receptor and its constitutively active, C-terminally truncated counterparts Q640X and AR-V7
Authors: Friedemann Zengerling
Anca Azoitei
Alexander Herweg
Florian Jentzmik
Marcus V. Cronauer
Publication date: 01-05-2016
Publisher: Springer Berlin Heidelberg
Published in: World Journal of Urology / Issue 5/2016
Print ISSN: 0724-4983
Electronic ISSN: 1433-8726
DOI: https://doi.org/10.1007/s00345-015-1674-5

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Inhibition of IGF-1R diminishes transcriptional activity of the androgen receptor and its constitutively active, C-terminally truncated counterparts Q640X and AR-V7

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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