Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2014

Open Access 01-12-2014 | Research

The role of high cell density in the promotion of neuroendocrine transdifferentiation of prostate cancer cells

Authors: Zuzana Pernicová, Eva Slabáková, Radek Fedr, Šárka Šimečková, Josef Jaroš, Tereza Suchánková, Jan Bouchal, Gvantsa Kharaishvili, Milan Král, Alois Kozubík, Karel Souček

Published in: Molecular Cancer | Issue 1/2014

Login to get access

Abstract

Background

Tumor heterogeneity and the plasticity of cancer cells present challenges for effective clinical diagnosis and therapy. Such challenges are epitomized by neuroendocrine transdifferentiation (NED) and the emergence of neuroendocrine-like cancer cells in prostate tumors. This phenomenon frequently arises from androgen-depleted prostate adenocarcinoma and is associated with the development of castration-resistant prostate cancer and poor prognosis.

Results

In this study, we showed that NED was evoked in both androgen receptor (AR)-positive and AR-negative prostate epithelial cell lines by growing the cells to a high density. Androgen depletion and high-density cultivation were both associated with cell cycle arrest and deregulated expression of several cell cycle regulators, such as p27Kip1, members of the cyclin D protein family, and Cdk2. Dual inhibition of Cdk1 and Cdk2 using pharmacological inhibitor or RNAi led to modulation of the cell cycle and promotion of NED. We further demonstrated that the cyclic adenosine 3′, 5′-monophosphate (cAMP)-mediated pathway is activated in the high-density conditions. Importantly, inhibition of cAMP signaling using a specific inhibitor of adenylate cyclase, MDL-12330A, abolished the promotion of NED by high cell density.

Conclusions

Taken together, our results imply a new relationship between cell cycle attenuation and promotion of NED and suggest high cell density as a trigger for cAMP signaling that can mediate reversible NED in prostate cancer cells.
Appendix
Available only for authorised users
Literature
1.
Nelson WG, De Marzo AM, Isaacs WB: Prostate cancer. N Engl J Med. 2003, 349: 366-381. 10.1056/NEJMra021562CrossRefPubMed
2.
Cindolo L, Cantile M, Vacherot F, Terry S, de la Taille A: Neuroendocrine differentiation in prostate cancer: from lab to bedside. Urol Int. 2007, 79: 287-296. 10.1159/000109711CrossRefPubMed
3.
Bhatia S, Frangioni JV, Hoffman RM, Iafrate AJ, Polyak K: The challenges posed by cancer heterogeneity. Nat Biotech. 2012, 30: 604-610. 10.1038/nbt.2294.CrossRef
4.
Abrahamsson PA: Neuroendocrine cells in tumour growth of the prostate. Endocr Relat Cancer. 1999, 6: 503-519. 10.1677/erc.0.0060503CrossRefPubMed
5.
Yuan TC, Veeramani S, Lin MF: Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells. Endocr Relat Cancer. 2007, 14: 531-547. 10.1677/ERC-07-0061CrossRefPubMed
6.
Yuan TC, Veeramani S, Lin FF, Kondrikou D, Zelivianski S, Igawa T, Karan D, Batra SK, Lin MF: Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. Endocr Relat Cancer. 2006, 13: 151-167. 10.1677/erc.1.01043CrossRefPubMed
7.
Ismail AH, Landry F, Aprikian AG, Chevalier S: Androgen ablation promotes neuroendocrine cell differentiation in dog and human prostate. Prostate. 2002, 51: 117-125. 10.1002/pros.10066CrossRef
8.
Deeble PD, Murphy DJ, Parsons SJ, Cox ME: Interleukin-6- and cyclic AMP-mediated signaling potentiates neuroendocrine differentiation of LNCaP prostate tumor cells. Mol Cell Biol. 2001, 21: 8471-8482. 10.1128/MCB.21.24.8471-8482.2001PubMedCentralCrossRefPubMed
9.
Yang X, Chen MW, Terry S, Vacherot F, Chopin DK, Bemis DL, Kitajewski J, Benson MC, Guo Y, Buttyan R: A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells. Cancer Res. 2005, 65: 5263-5271. 10.1158/0008-5472.CAN-05-0162CrossRefPubMed
10.
Cortes MA, Cariaga-Martinez AE, Lobo MV, Martin Orozco RM, Motino O, Rodriguez-Ubreva FJ, Angulo J, Lopez-Ruiz P, Colas B: EGF promotes neuroendocrine-like differentiation of prostate cancer cells in the presence of LY294002 through increased ErbB2 expression independent of the phosphatidylinositol 3-kinase-AKT pathway. Carcinogenesis. 2012, 33: 1169-1177. 10.1093/carcin/bgs139CrossRefPubMed
11.
Cox ME, Deeble PD, Bissonette EA, Parsons SJ: Activated 3′, 5′-cyclic AMP-dependent protein kinase is sufficient to induce neuroendocrine-like differentiation of the LNCaP prostate tumor cell line. J Biol Chem. 2000, 275: 13812-13818. 10.1074/jbc.275.18.13812CrossRefPubMed
12.
Zelivianski S, Verni M, Moore C, Kondrikov D, Taylor R, Lin MF: Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype. Biochim Biophys Acta. 2001, 1539: 28-43. 10.1016/S0167-4889(01)00087-8CrossRefPubMed
13.
Cantile M, Kisslinger A, Cindolo L, Schiavo G, D’Anto V, Franco R, Altieri V, Gallo A, Villacci A, Tramontano D, Cillo C: cAMP induced modifications of HOX D gene expression in prostate cells allow the identification of a chromosomal area involved in vivo with neuroendocrine differentiation of human advanced prostate cancers. J Cell Physiol. 2005, 205: 202-210.CrossRefPubMed
14.
Deng X, Liu H, Huang J, Cheng L, Keller ET, Parsons SJ, Hu CD: Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: implications for disease progression. Cancer Res. 2008, 68: 9663-9670. 10.1158/0008-5472.CAN-08-2229PubMedCentralCrossRefPubMed
15.
Deng X, Elzey BD, Poulson JM, Morrison WB, Ko SC, Hahn NM, Ratliff TL, Hu CD: Ionizing radiation induces neuroendocrine differentiation of prostate cancer cells in vitro, in vivo and in prostate cancer patients. Am J Cancer Res. 2011, 1: 834-844.PubMedCentralPubMed
16.
Knudsen KE, Arden KC, Cavenee WK: Multiple G1 regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells. J Biol Chem. 1998, 273: 20213-20222. 10.1074/jbc.273.32.20213CrossRefPubMed
17.
18.
Fribourg AF, Knudsen KE, Strobeck MW, Lindhorst CM, Knudsen ES: Differential requirements for ras and the retinoblastoma tumor suppressor protein in the androgen dependence of prostatic adenocarcinoma cells. Cell Growth Differ. 2000, 11: 361-372.PubMed
19.
Orbo A, Jaeger R, Sager G: Cell density dependence of cAMP and cGMP levels in four human cell lines derived from carcinomas of the uterine cervix. Gynecol Oncol. 1994, 52: 320-325. 10.1006/gyno.1994.1056CrossRefPubMed
20.
Piast M, Kustrzeba-Wojcicka I, Matusiewicz M, Banas T: Molecular evolution of enolase. Acta Biochim Pol. 2005, 52: 507-513.PubMed
21.
Easter SS, Ross LS, Frankfurter A: Initial tract formation in the mouse brain. J Neurosci. 1993, 13: 285-299.PubMed
22.
Koshimizu H, Kim T, Cawley NX, Loh YP: Chromogranin A: a new proposal for trafficking, processing and induction of granule biogenesis. Regul Pept. 2010, 160: 153-159. 10.1016/j.regpep.2009.12.007PubMedCentralCrossRefPubMed
23.
Wafa LA, Cheng H, Rao MA, Nelson CC, Cox M, Hirst M, Sadowski I, Rennie PS: Isolation and identification of L-dopa decarboxylase as a protein that binds to and enhances transcriptional activity of the androgen receptor using the repressed transactivator yeast two-hybrid system. Biochem J. 2003, 375: 373-383. 10.1042/BJ20030689PubMedCentralCrossRefPubMed
24.
Marchiani S, Tamburrino L, Nesi G, Paglierani M, Gelmini S, Orlando C, Maggi M, Forti G, Baldi E: Androgen-responsive and -unresponsive prostate cancer cell lines respond differently to stimuli inducing neuroendocrine differentiation. Int J Androl. 2010, 33: 784-793. 10.1111/j.1365-2605.2009.01030.xCrossRefPubMed
25.
Terry S, Ploussard G, Allory Y, Nicolaiew N, Boissiere-Michot F, Maille P, Kheuang L, Coppolani E, Ali A, Bibeau F, Culine S, Buttyan R, de la Taille A, Vacherot F: Increased expression of class III beta-tubulin in castration-resistant human prostate cancer. Br J Cancer. 2009, 101: 951-956. 10.1038/sj.bjc.6605245PubMedCentralCrossRefPubMed
26.
Wafa LA, Palmer J, Fazli L, Hurtado-Coll A, Bell RH, Nelson CC, Gleave ME, Cox ME, Rennie PS: Comprehensive expression analysis of L-dopa decarboxylase and established neuroendocrine markers in neoadjuvant hormone-treated versus varying Gleason grade prostate tumors. Hum Pathol. 2007, 38: 161-170. 10.1016/j.humpath.2006.07.003CrossRefPubMed
27.
Cox ME, Deeble PD, Lakhani S, Parsons SJ: Acquisition of neuroendocrine characteristics by prostate tumor cells is reversible: implications for prostate cancer progression. Cancer Res. 1999, 59: 3821-3830.PubMed
28.
Vindrieux D, Reveiller M, Florin A, Blanchard C, Ruffion A, Devonec M, Benahmed M, Grataroli R: TNF-alpha-related apoptosis-inducing ligand decoy receptor DcR2 is targeted by androgen action in the rat ventral prostate. J Cell Physiol. 2006, 206: 709-717. 10.1002/jcp.20520CrossRefPubMed
29.
Vindrieux D, Reveiller M, Chantepie J, Yakoub S, Deschildre C, Ruffion A, Devonec M, Benahmed M, Grataroli R: Down-regulation of DcR2 sensitizes androgen-dependent prostate cancer LNCaP cells to TRAIL-induced apoptosis. Cancer Cell Int. 2011, 11: 42- 10.1186/1475-2867-11-42PubMedCentralCrossRefPubMed
30.
Neuwirt H, Puhr M, Cavarretta IT, Mitterberger M, Hobisch A, Culig Z: Suppressor of cytokine signalling-3 is up-regulated by androgen in prostate cancer cell lines and inhibits androgen-mediated proliferation and secretion. Endocr Relat Cancer. 2007, 14: 1007-1019. 10.1677/ERC-07-0172CrossRefPubMed
31.
Evans MJ, Smith-Jones PM, Wongvipat J, Navarro V, Kim S, Bander NH, Larson SM, Sawyers CL: Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci U S A. 2011, 108: 9578-9582. 10.1073/pnas.1106383108PubMedCentralCrossRefPubMed
32.
Macdonald JI, Dick FA: Posttranslational modifications of the retinoblastoma tumor suppressor protein as determinants of function. Genes Cancer. 2012, 3: 619-633. 10.1177/1947601912473305PubMedCentralCrossRefPubMed
33.
Lincova E, Hampl A, Pernicova Z, Starsichova A, Krcmar P, Machala M, Kozubik A, Soucek K: Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs. Biochem Pharmacol. 2009, 78: 561-572. 10.1016/j.bcp.2009.05.001CrossRefPubMed
34.
Brooks EE, Gray NS, Joly A, Kerwar SS, Lum R, Mackman RL, Norman TC, Rosete J, Rowe M, Schow SR, Schultz PG, Wang X, Wick MM, Shiffman D: CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation. J Biol Chem. 1997, 272: 29207-29211. 10.1074/jbc.272.46.29207CrossRefPubMed
35.
Bang YJ, Pirnia F, Fang WG, Kang WK, Sartor O, Whitesell L, Ha MJ, Tsokos M, Sheahan MD, Nguyen P, Niklinski WT, Myers CE, Trepel JB: Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP. Proc Natl Acad Sci U S A. 1994, 91: 5330-5334. 10.1073/pnas.91.12.5330PubMedCentralCrossRefPubMed
36.
Sharifi N, Gulley JL, Dahut WL: An update on androgen deprivation therapy for prostate cancer. Endocr Relat Cancer. 2010, 17: R305-R315. 10.1677/ERC-10-0187PubMedCentralCrossRefPubMed
37.
Xu Y, Chen SY, Ross KN, Balk SP: Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res. 2006, 66: 7783-7792. 10.1158/0008-5472.CAN-05-4472CrossRefPubMed
38.
Pernicova Z, Slabakova E, Kharaishvili G, Bouchal J, Kral M, Kunicka Z, Machala M, Kozubik A, Soucek K: Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2. Neoplasia. 2011, 13: 526-536.PubMedCentralCrossRefPubMed
39.
40.
Cindolo L, Cantile M, Franco R, Chiodini P, Schiavo G, Forte I, Zlobec I, Salzano L, Botti G, Gidaro S, Terracciano L, Cillo C: Parallel determination of NeuroD1, chromogranin-A, KI67 and androgen receptor expression in surgically treated prostate cancers. Int Braz J Urol. 2011, 37: 57-66. 10.1590/S1677-55382011000100008CrossRefPubMed
41.
Cindolo L, Franco R, Cantile M, Schiavo G, Liguori G, Chiodini P, Salzano L, Autorino R, Di Blasi A, Falsaperla M, Feudale E, Botti G, Gallo A, Cillo C: NeuroD1 expression in human prostate cancer: can it contribute to neuroendocrine differentiation comprehension?. Eur Urol. 2007, 52: 1365-1373. 10.1016/j.eururo.2006.11.030CrossRefPubMed
42.
Bubendorf L, Sauter G, Moch H, Schmid H-P, Gasser TC, Jordan P, Mihatsch MJ: Ki-67 labeling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy. J Pathol. 1996, 178: 437-441. 10.1002/(SICI)1096-9896(199604)178:4<437::AID-PATH484>3.0.CO;2-4CrossRefPubMed
43.
Grobholz R, Griebe M, Sauer CG, Michel MS, Trojan L, Bleyl U: Influence of neuroendocrine tumor cells on proliferation in prostatic carcinoma. Hum Pathol. 2005, 36: 562-570. 10.1016/j.humpath.2005.02.019CrossRefPubMed
44.
Mori S, Murakami-Mori K, Bonavida B: Interleukin-6 induces G1 arrest through induction of p27(Kip1), a cyclin-dependent kinase inhibitor, and neuron-like morphology in LNCaP prostate tumor cells. Biochem Biophys Res Commun. 1999, 257: 609-614. 10.1006/bbrc.1999.0515CrossRefPubMed
45.
Taneja SS, Ha S, Garabedian MJ: Androgen stimulated cellular proliferation in the human prostate cancer cell line LNCaP is associated with reduced retinoblastoma protein expression. J Cell Biochem. 2001, 84: 188-199.CrossRefPubMed
46.
Tyagi A, Agarwal C, Agarwal R: Inhibition of retinoblastoma protein (Rb) phosphorylation at serine sites and an increase in Rb-E2F complex formation by silibinin in androgen-dependent human prostate carcinoma LNCaP cells: role in prostate cancer prevention. Mol Cancer Ther. 2002, 1: 525-532.PubMed
47.
Vassilev LT, Tovar C, Chen S, Knezevic D, Zhao X, Sun H, Heimbrook DC, Chen L: Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1. Proc Natl Acad Sci U S A. 2006, 103: 10660-10665. 10.1073/pnas.0600447103PubMedCentralCrossRefPubMed
48.
Pitts TM, Davis SL, Eckhardt SG, Bradshaw-Pierce EL: Targeting nuclear kinases in cancer: Development of cell cycle kinase inhibitors. Pharmacol Ther. 2014, 142: 258-269. 10.1016/j.pharmthera.2013.12.010CrossRefPubMed
49.
Santore TA, Chen Y, Smit MJ, Iyengar R: Adenovirus-directed expression of Q227L-G alpha(s) inhibits growth of established tumors of later-stage human breast cancer cells in athymic mice. Proc Natl Acad Sci U S A. 2002, 99: 1671-1676. 10.1073/pnas.032661999PubMedCentralCrossRefPubMed
50.
Ugland H, Boquest AC, Naderi S, Collas P, Blomhoff HK: cAMP-mediated induction of cyclin E sensitizes growth-arrested adipose stem cells to DNA damage-induced apoptosis. Mol Biol Cell. 2008, 19: 5082-5092. 10.1091/mbc.E08-01-0094PubMedCentralCrossRefPubMed
51.
Horoszewicz JS, Leong SS, Chu TM, Wajsman ZL, Friedman M, Papsidero L, Kim U, Chai LS, Kakati S, Arya SK, Sandberg AA: The LNCaP cell line–a new model for studies on human prostatic carcinoma. Prog Clin Biol Res. 1980, 37: 115-132.PubMed
52.
Veldscholte J, Berrevoets CA, Ris-Stalpers C, Kuiper GG, Jenster G, Trapman J, Brinkmann AO, Mulder E: The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol. 1992, 41: 665-669. 10.1016/0960-0760(92)90401-4CrossRefPubMed
53.
Klein KA, Reiter RE, Redula J, Moradi H, Zhu XL, Brothman AR, Lamb DJ, Marcelli M, Belldegrun A, Witte ON, Sawyers CL: Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat Med. 1997, 3: 402-408. 10.1038/nm0497-402CrossRefPubMed
54.
Wu HC, Hsieh JT, Gleave ME, Brown NM, Pathak S, Chung LW: Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells. Int J Cancer. 1994, 57: 406-412. 10.1002/ijc.2910570319CrossRefPubMed
55.
Hayward SW, Dahiya R, Cunha GR, Bartek J, Deshpande N, Narayan P: Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1. In Vitro Cell Dev Biol Anim. 1995, 31: 14-24. 10.1007/BF02631333CrossRefPubMed
56.
Hayward SW, Wang Y, Cao M, Hom YK, Zhang B, Grossfeld GD, Sudilovsky D, Cunha GR: Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res. 2001, 61: 8135-8142.PubMed
57.
Slabakova E, Pernicova Z, Slavickova E, Starsichova A, Kozubik A, Soucek K: TGF-beta1-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2/Slug. Prostate. 2011, 71: 1332-1343.PubMed
58.
Schmittgen TD, Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008, 3: 1101-1108. 10.1038/nprot.2008.73CrossRefPubMed
Metadata
Title
The role of high cell density in the promotion of neuroendocrine transdifferentiation of prostate cancer cells
Authors
Zuzana Pernicová
Eva Slabáková
Radek Fedr
Šárka Šimečková
Josef Jaroš
Tereza Suchánková
Jan Bouchal
Gvantsa Kharaishvili
Milan Král
Alois Kozubík
Karel Souček
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-13-113

Other articles of this Issue 1/2014

Molecular Cancer 1/2014 Go to the issue

Research

Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling

Research

miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer

Research

Ponatinib efficiently kills imatinib-resistant chronic eosinophilic leukemia cells harboring gatekeeper mutant T674I FIP1L1-PDGFRα: roles of Mcl-1 and β-catenin

Research

Claudin-low breast cancers: clinical, pathological, molecular and prognostic characterization

Research

OTUB1 promotes metastasis and serves as a marker of poor prognosis in colorectal cancer

Research

Vasohibin-2 modulates tumor onset in the gastrointestinal tract by normalizing tumor angiogenesis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits