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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2012

Open Access 01-12-2012 | Primary research

Neuropeptide-inducible upregulation of proteasome activity precedes nuclear factor kappa B activation in androgen-independent prostate cancer cells

Authors: Anna Patrikidou, Panagiotis J Vlachostergios, Ioannis A Voutsadakis, Eleana Hatzidaki, Rosalia-Maria Valeri, Chariklia Destouni, Effie Apostolou, Christos N Papandreou

Published in: Cancer Cell International | Issue 1/2012

Login to get access

Abstract

Background

Upregulation of nuclear factor kappa B (NFκB) activity and neuroendocrine differentiation are two mechanisms known to be involved in prostate cancer (PC) progression to castration resistance. We have observed that major components of these pathways, including NFκB, proteasome, neutral endopeptidase (NEP) and endothelin 1 (ET-1), exhibit an inverse and mirror image pattern in androgen-dependent (AD) and -independent (AI) states in vitro.

Methods

We have now investigated for evidence of a direct mechanistic connection between these pathways with the use of immunocytochemistry (ICC), western blot analysis, electrophoretic mobility shift assay (EMSA) and proteasome activity assessment.

Results

Neuropeptide (NP) stimulation induced nuclear translocation of NFκB in a dose-dependent manner in AI cells, also evident as reduced total inhibitor κB (IκB) levels and increased DNA binding in EMSA. These effects were preceded by increased 20 S proteasome activity at lower doses and at earlier times and were at least partially reversed under conditions of NP deprivation induced by specific NP receptor inhibitors, as well as NFκB, IκB kinase (IKK) and proteasome inhibitors. AD cells showed no appreciable nuclear translocation upon NP stimulation, with less intense DNA binding signal on EMSA.

Conclusions

Our results support evidence for a direct mechanistic connection between the NPs and NFκB/proteasome signaling pathways, with a distinct NP-induced profile in the more aggressive AI cancer state.
Appendix
Available only for authorised users
Literature
1.
Papandreou CN, Logothetis CJ: Bortezomib as a potential treatment for prostate cancer. Cancer Res. 2004, 64: 5036-5043. 10.1158/0008-5472.CAN-03-2707.CrossRefPubMed
2.
Ross JS, Kallakury BV, Sheehan CE, Fisher HA, Kaufman RP, Kaur P, Gray K, Stringer B: Expression of nuclear factor-kappa B and I kappa B alpha proteins in prostatic adenocarcinomas: correlation of nuclear factor-kappa B immunoreactivity with disease recurrence. Clin Cancer Res. 2004, 10: 2466-2472. 10.1158/1078-0432.CCR-0543-3.CrossRefPubMed
3.
Paule B, Terry S, Kheuang L, Soyeux P, Vacherot F, de la Taille A: The NF-kappaB/IL-6 pathway in metastatic androgen-independent prostate cancer: new therapeutic approaches?. World J Urol. 2007, 25: 477-489. 10.1007/s00345-007-0175-6.CrossRefPubMed
4.
Spiotto MT, Chung TD: STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate. 2000, 42: 186-195. 10.1002/(SICI)1097-0045(20000215)42:3<186::AID-PROS4>3.0.CO;2-E.CrossRefPubMed
5.
Sanford DC, Dewille JW: C/EBPdelta is a downstream mediator of IL-6 induced growth inhibition of prostate cancer cells. Prostate. 2005, 63: 143-154. 10.1002/pros.20159.CrossRefPubMed
6.
Jin RJ, Lho Y, Connelly L, Wang Y, Yu X, Saint Jean L, Case TC, Ellwood-Yen K, Sawyers CL, Bhowmick NA, Blackwell TS, Yull FE, Matusik RJ: The nuclear factor-kappaB pathway controls the progression of prostate cancer to androgen-independent growth. Cancer Res. 2008, 68: 6762-6729. 10.1158/0008-5472.CAN-08-0107.PubMedCentralCrossRefPubMed
7.
Chen ZJ: Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol. 2005, 7: 759-763.
8.
DeMartino GN, Gillette TG: Proteasomes: machines for all reasons. Cell. 2007, 129: 659-662. 10.1016/j.cell.2007.05.007.CrossRefPubMed
9.
Vlachostergios PJ, Patrikidou A, Daliani DD, Papandreou CN: The ubiquitin-proteasome system in cancer, a major player in DNA repair. Part 1: post-translational regulation. J Cell Mol Med. 2009, 13: 3006-3018. 10.1111/j.1582-4934.2009.00824.x.PubMedCentralCrossRefPubMed
10.
Vlachostergios PJ, Patrikidou A, Daliani DD, Papandreou CN: The ubiquitin-proteasome system in cancer, a major player in DNA repair. Part 2: transcriptional regulation. J Cell Mol Med. 2009, 13: 3019-3031. 10.1111/j.1582-4934.2009.00825.x.PubMedCentralCrossRefPubMed
11.
Shipp MA, Tarr GE, Chen CY, Switzer SN, Hersh LB, Steins H, Sundays ME, Reinherz EL: CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung. Proc Natl Acad Sci USA. 1991, 88: 10662-10666. 10.1073/pnas.88.23.10662.PubMedCentralCrossRefPubMed
12.
Shipp MA, Look AT: Hematopoietic differentiation antigens that are membrane-associated enzymes: cutting is the key!. Blood. 1993, 84: 1052-1070.
13.
Turner AJ, Isaac RE, Coates D: The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function. BioEssays. 2001, 23: 261-269. 10.1002/1521-1878(200103)23:3<261::AID-BIES1036>3.0.CO;2-K.CrossRefPubMed
14.
King KA, Hua J, Torday JS, Drazen JM, Graham SA, Shipp MA, Sunday ME: CD10/neutral endopeptidase 24.11 regulates fetal lung growth and maturation in utero by potentiating endogenous bombesin-like peptides. J Clin Investig. 1993, 91: 1969-1973. 10.1172/JCI116417.PubMedCentralCrossRefPubMed
15.
Bologna M, Festuccia C, Muzi P, Biordi L, Ciomei M: Bombesin stimulates growth of human prostatic cancer cells in vitro. Cancer. 1989, 63: 1714-1720.CrossRefPubMed
16.
Nelson JB, Hedican SP, George DJ, Reddi AH, Piantadosi S, Eisenberg MA, Simons JW: Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med. 1995, 1: 944-949. 10.1038/nm0995-944.CrossRefPubMed
17.
Nelson JB, Chan-Tack K, Hedican SP, Magnuson SR, Opgenorth TJ, Bova GS, Simons JW: Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer. Cancer Res. 1996, 56: 663-668.PubMed
18.
Godara G, Pecher S, Jukic DM, D’ Antonio JM, Akhavan A, Nelson JB, Pflug BR: Distinct patterns of endothelin axis expression in primary prostate cancer. Urology. 2007, 70: 209-215.CrossRefPubMed
19.
Aprikian AG, Tremblay L, Han K, Chevalier S: Bombesin stimulates the motility of human prostate-carcinoma cells through tyrosine phosphorylation of focal adhesion kinase and of integrin-associated proteins. Int J Cancer. 1997, 72: 498-504. 10.1002/(SICI)1097-0215(19970729)72:3<498::AID-IJC19>3.0.CO;2-8.CrossRefPubMed
20.
Festuccia C, Guerra F, D’Ascenzo S, Giunciuglio D, Albini A, Bologna M: In vitro regulation of pericellular proteolysis in prostatic tumor cells treated with bombesin. Int J Cancer. 1998, 75: 418-431. 10.1002/(SICI)1097-0215(19980130)75:3<418::AID-IJC16>3.0.CO;2-4.CrossRefPubMed
21.
Dai J, Shen R, Sumitomo M, Goldberg JS, Geng Y, Navarro D, Xu S, Koutcher JA, Garzotto M, Powell CT, Nanus DM: Tumor-suppressive effects of neutral endopeptidase in androgen-independent prostate cancer cells. Clin Cancer Res. 2001, 7: 1370-1377.PubMed
22.
Sumitomo M, Milowsky MI, Shen R, Navarro D, Dai J, Asano T, Hayakawa M, Nanus DM: Neutral endopeptidase inhibits neuropeptide-mediated transactivation of the insulin-like growth factor receptor-Akt cell survival pathway. Cancer Res. 2001, 61: 3294-3298.PubMed
23.
Levine L, Lucci JA, Pazdrak B, Cheng JZ, Guo YS, Townsend CM, Hellmich MR: Bombesin stimulates nuclear factor kappa B activation and expression of proangiogenic factors in prostate cancer cells. Cancer Res. 2003, 63: 3495-3502.PubMed
24.
Dawson LA, Maitland NJ, Turner AJ, Usmani BA: Stromal–epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression. Br J Cancer. 2006, 90: 1577-1582.CrossRef
25.
Battistini B, Chailler P, D’Orléans-Juste P, Brière N, Sirois P: Growth regulatory properties of endothelins. Peptides. 1993, 14: 385-389. 10.1016/0196-9781(93)90057-N.CrossRefPubMed
26.
Steiner MS: Role of peptide growth factors in prostate. Urology. 1993, 42: 88-110.CrossRef
27.
Reile H, Armatis PE, Schally AV: Characterization of high-affinity receptors for bombesin/gastrin releasing peptide on the human prostate:ancer cell lines PC-3 and DU-145: internalization of receptor bound 125I-(Tyr4) bombesin by tumor cells. Prostate. 1994, 25: 29-38. 10.1002/pros.2990250105.CrossRefPubMed
28.
Aprikian AG, Han K, Chevalier S, Bazinet M, Viallet J: Bombesin specifically induces intracellular calcium mobilization via gastrin-releasing peptide receptors in human prostate cancer cells. J Mol Endocrinol. 1996, 16: 297-306. 10.1677/jme.0.0160297.CrossRefPubMed
29.
Markwalder R, Reubi JC: Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res. 1999, 59: 1152-1159.PubMed
30.
Sun B, Halmos G, Schally AV, Wang X, Martinez M: Presence of receptors for bombesin/gastrin-releasing peptide and mRNA for three receptor subtypes in human PCs. Prostate. 2000, 42: 295-303. 10.1002/(SICI)1097-0045(20000301)42:4<295::AID-PROS7>3.0.CO;2-B.CrossRefPubMed
31.
Papandreou CN, Usmani BA, Geng Y, Bogenreider T, Freeman R, Wilk S, Finstad CL, Reuter VE, Powell CT, Scheinberg D, Magill C, Scher HI, Albino AP, Nanus DM: Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression. Nat Med. 1998, 4: 50-57. 10.1038/nm0198-050.CrossRefPubMed
32.
Usmani BA, Shen R, Janeczko M, Papandreou CN, Lee WH, Nelson WG, Nelson JB, Nanus DM: Methylation of the neutral endopeptidase gene promoter in human prostate cancers. Clin Cancer Res. 2000, 6: 1664-1670.PubMed
33.
Shen R, Sumitomo M, Dai J, Harris A, Kaminetzky D, Gao M, Burnstein KL, Nanus DM: Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase. Endocrinol. 2000, 141: 1699-1704. 10.1210/en.141.5.1699.
34.
Shen R, Sumitomo M, Dai J, Hardy DO, Navarro D, Usmani B, Papandreou CN, Hersh LB, Shipp MA, Freedman LP, Nanus DM: Identification and characterization of two androgen response regions in the human neutral endopeptidase gene. Mol Cell Endocrinol. 2000, 170: 131-142. 10.1016/S0303-7207(00)00326-9.CrossRefPubMed
35.
Nanus DM: Of peptides and peptidases: the role of cell surface peptidases in cancer. Clin Cancer Res. 2003, 9: 6307-6309.PubMed
36.
Sumitomo M, Tachibana M, Nakashima J, Murai M, Miyajima A, Kimura F, Hayakawa M, Nakamura H: An essential role for nuclear factor kappa B in preventing TNF-α-induced cell death in prostate cancer cells. J Urol. 1999, 161: 674-679. 10.1016/S0022-5347(01)61993-1.CrossRefPubMed
37.
Muenchen HJ, Lin DL, Walsh MA, Keller ET, Pienta KJ: Tumor necrosis factor-alpha-induced apoptosis in prostate cancer cells through inhibition of nuclear factor-kappaB by an IkappaBalpha “super-repressor”. Clin Cancer Res. 2000, 6: 1969-1977.PubMed
38.
Lindholm PF, Bub J, Kaul S, Shidham VB, Kajdacsy-Balla A: The role of constitutive NF-kappaB activity in PC-3 human prostate cancer cell invasive behavior. Clin Exp Metastasis. 2001, 18: 471-479.CrossRef
39.
Gasparian AV, Yao YJ, Kowalczyk D, Lyakh LA, Karseladze A, Slaga TJ, Budunova IV: The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells. J Cell Sci. 2002, 115: 141-151.PubMed
40.
Patrikidou A, Vlachostergios PJ, Voutsadakis IA, Hatzidaki E, Valeri RM, Destouni C, Apostolou E, Daliani D, Papandreou CN: Inverse baseline expression pattern of the NEP/neuropeptides and NFkappaB/proteasome pathways in androgen-dependent and androgen-independent prostate cancer cells. Cancer Cell Int. 2011, 11: 13-10.1186/1475-2867-11-13.PubMedCentralCrossRefPubMed
41.
Carter AB, Monick MM, Hunninghake GW: Lipopolysaccharide-induced NF-kappaB activation and cytokine release in human alveolar macrophages is PKC-independent and TK- and PC-PLC–dependent. Am J Respir Cell Mol Biol. 1998, 18: 384-391.CrossRefPubMed
42.
Ouadrhiri Y, Pilette C, Monteiro RC, Vaerman JP, Sibille Y: Effect of IgA on respiratory burst and cytokine release by human alveolar macrophages: role of ERK1/2 mitogen-activated protein kinases and NF-kappaB. Am J Respir Cell Mol Biol. 2002, 26: 315-332.CrossRefPubMed
43.
Abramoff MD, Magelhaes PJ, Ram SJ: Image Processing with ImageJ. Biophotonics International. 2004, 11: 36-42.
44.
Thanos D, Maniatis T: Identification of the rel family members required for family inductions of the human beta interferon gene. Mol Cell Biol. 1995, 15: 152-164.PubMedCentralCrossRefPubMed
45.
Tsapakidis K, Vlachostergios PJ, Voutsadakis IA, Befani CD, Patrikidou A, Hatzidaki E, Daliani DD, Moutzouris G, Liakos P, Papandreou CN: Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells. Int J Urol. 2012, 10.1111/j.1442-2042.2012.02967.x. Epub ahead of print
46.
de Visser M, Bernard HF, Erion JL, Schmidt MA, Srinivasan A, Waser B, Reubi JC, Krenning EP, de Jung M: Novel 111In-labelled bombesin analogues for molecular imaging of prostate tumours. Eur J Nucl Med Mol Imaging. 2007, 34: 1228-1238. 10.1007/s00259-006-0356-3.CrossRefPubMed
47.
Le Page C, Koumakpayi IH, Lessard L, Mes-Masson AM, Saad F: EGFR and Her-2 regulate the constitutive activation of NF-kappaB in PC-3 prostate cancer cells. Prostate. 2005, 65: 130-140. 10.1002/pros.20234.CrossRefPubMed
48.
Kukreja P, Abdel-Mageed AB, Mondal D, Liu K, Agrawal KC: Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-1alpha (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-kappaB activation. Cancer Res. 2005, 65: 9891-9898. 10.1158/0008-5472.CAN-05-1293.CrossRefPubMed
49.
Suh J, Payvandi F, Edelstein LC, Amenta PS, Zong WX, Gélinas C, Rabson AB: Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells. Prostate. 2002, 52: 183-200. 10.1002/pros.10082.CrossRefPubMed
50.
Browatzki M, Schmidt J, Kübler W, Kranzhöfer R: Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-kappaB in human vascular smooth muscle cells. Basic Res Cardiol. 2002, 95: 98-105.CrossRef
51.
Banerjee S, Hussain M, Wang Z, Saliganan A, Che M, Bonfil D, Cher M, Sarkar FH: In vitro and in vivo molecular evidence for better therapeutic efficacy of ABT-627 and taxotere combination in prostate cancer. Cancer Res. 2007, 67: 3818-3826. 10.1158/0008-5472.CAN-06-3879.CrossRefPubMed
52.
Usmani B, Harden B, Maitland NJ, Turner AJ: Differential expression of neutral endopeptidase-24.11 (neprilysin) and endothelin-converting enzyme in human prostate cancer cell lines. Clin Sci. 2002, 103: 3145-3175.CrossRef
Metadata
Title
Neuropeptide-inducible upregulation of proteasome activity precedes nuclear factor kappa B activation in androgen-independent prostate cancer cells
Authors
Anna Patrikidou
Panagiotis J Vlachostergios
Ioannis A Voutsadakis
Eleana Hatzidaki
Rosalia-Maria Valeri
Chariklia Destouni
Effie Apostolou
Christos N Papandreou
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2012
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-12-31

Other articles of this Issue 1/2012

Cancer Cell International 1/2012 Go to the issue

Primary research

The tumour metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocase

Primary research

Toxicities effects of pharmaceutical, olive mill and textile wastewaters before and after degradation by Pseudomonas putida mt-2

Primary research

Quercetin-induced inhibition and synergistic activity with cisplatin – a chemotherapeutic strategy for nasopharyngeal carcinoma cells

Primary research

Cancer stem cells from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall

Primary research

Inhibition of breast cancer cell proliferation in repeated and non-repeated treatment with zoledronic acid

Primary research

Lycorine induces cell-cycle arrest in the G0/G1 phase in K562 cells via HDAC inhibition
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