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

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 3/2008

Open Access 01-06-2008 | Research article

TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cells

Authors: Ann-Marie Simeone, Vanity McMurtry, René Nieves-Alicea, Joseph E Saavedra, Larry K Keefer, Marcella M Johnson, Ana M Tari

Published in: Breast Cancer Research | Issue 3/2008

Login to get access

Abstract

Introduction

Tumor invasion and metastasis remain a major cause of mortality in breast cancer patients. High concentrations of nitric oxide (NO) suppress tumor invasion and metastasis in vivo. NO prodrugs generate large amounts of NO upon metabolism by appropriate intracellular enzymes, and therefore could have potential in the prevention and therapy of metastatic breast cancer.

Methods

The present study was designed to determine the effects of the NO-releasing prodrug O2-(2,4-dinitrophenyl) 1- [(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) on breast cancer invasion and the mechanisms involved. MDA-MB-231, MDA-MB-231/F10, and MCF-7/COX-2 were the three breast cancer cell lines tested. NO levels were determined spectrophotometrically using a NO assay kit. Invasion and the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs were determined using Matrigel invasion assays, an MMP array kit and ELISAs. The activity and expression of extracellular signal-regulated kinase 1/2, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases were determined using western blot analyses.

Results

Under conditions by which JS-K was not cytotoxic, JS-K significantly decreased (P < 0.05) the invasiveness of breast cancer cells across the Matrigel basement membrane, which was directly correlated with NO production. JS-43-126, a non-NO-releasing analog of JS-K, had no effect on NO levels or invasion. JS-K increased (P < 0.05) TIMP-2 production, and blocking TIMP-2 activity with a neutralizing antibody significantly increased (P < 0.05) the invasive activity of JS-K-treated cells across Matrigel. JS-K decreased p38 activity, whereas the activity and the expression of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase were unaffected.

Conclusion

We report the novel findings that JS-K inhibits breast cancer invasion across the Matrigel basement membrane, and NO production is vital for this activity. Upregulation of TIMP-2 production is one mechanism by which JS-K mediates its anti-invasive effects. JS-K and other NO prodrugs may represent an innovative biological approach in the prevention and treatment of metastatic breast cancer.
Appendix
Available only for authorised users
Literature
1.
2.
Orucevic A, Bechberger J, Green AM, Shapiro RA, Billiar TR, Lala PK: Nitric-oxide production by murine mammary adenocarcinoma cells promotes tumor-cell invasiveness. Int J Cancer. 1999, 81: 889-896. 10.1002/(SICI)1097-0215(19990611)81:6<889::AID-IJC9>3.0.CO;2-2.CrossRefPubMed
3.
Jadeski LC, Hum KO, Chakraborty C, Lala PK: Nitric oxide promotes murine mammary tumour growth and metastasis by stimulating tumour cell migration, invasiveness and angiogenesis. Int J Cancer. 2000, 86: 30-39. 10.1002/(SICI)1097-0215(20000401)86:1<30::AID-IJC5>3.0.CO;2-I.CrossRefPubMed
4.
Xie K, Huang S, Dong Z, Juang SH, Gutman M, Xie QW, Nathan C, Fidler IJ: Transfection with the inducible nitric oxide synthase gene suppresses tumorigenicity and abrogates metastasis by K-1735 murine melanoma cells. J Exp Med. 1995, 181: 1333-1343. 10.1084/jem.181.4.1333.CrossRefPubMed
5.
Dhar A, Brindley JM, Stark C, Citro ML, Keefer LK, Colburn NH: Nitric oxide does not mediate but inhibits transformation and tumor phenotype. Mol Cancer Ther. 2003, 2: 1285-1293.PubMed
6.
Gauthier N, Lohm S, Touzery C, Chantome A, Perette B, Reveneau S, Brunotte F, Juillerat-Jeanneret L, Jeannin JF: Tumour-derived and host-derived nitric oxide differentially regulate breast carcinoma metastasis to the lungs. Carcinogenesis. 2004, 25: 1559-1565. 10.1093/carcin/bgh158.CrossRefPubMed
7.
Harada K, Supriatno , Kawaguchi S, Tomitaro O, Yoshida H, Sato M: Overexpression of iNOS gene suppresses the tumorigenicity and metastasis of oral cancer cells. In Vivo. 2004, 18: 449-455.PubMed
8.
Le X, Wei D, Huang S, Lancaster JR, Xie K: Nitric oxide synthase II suppresses the growth and metastasis of human cancer regardless of its up-regulation of protumor factors. Proc Natl Acad Sci USA. 2005, 102: 8758-8763. 10.1073/pnas.0409581102.CrossRefPubMedPubMedCentral
9.
Simeone A-M, Broemeling L, Rosenblum J, Tari AM: HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production. Oncogene. 2003, 22: 6739-6747. 10.1038/sj.onc.1206786.CrossRefPubMed
10.
Simeone A-M, Li YJ, Broemeling LD, Johnson MM, Tuna M, Tari AM: Cyclooxygenase-2 is essential for HER2/neu to suppress N-(4-hydroxyphenyl)retinamide apoptotic effects in breast cancer cells. Cancer Res. 2004, 64: 1224-1228. 10.1158/0008-5472.CAN-03-2188.CrossRefPubMed
11.
Howie AF, Miller WR, Hawkins RA, Hutchinson AR, Beckett GJ: Expression of glutathione S-transferase B1, B2, Mu and Pi in breast cancers and their relationship to oestrogen receptor status. Br J Cancer. 1989, 60: 834-837.CrossRefPubMedPubMedCentral
12.
Shea TC, Claflin G, Comstock KE, Sanderson BJ, Burstein NA, Keenan EJ, Mannervik B, Henner WD: Glutathione transferase activity and isoenzyme composition in primary human breast cancers. Cancer Res. 1990, 50: 6848-6853.PubMed
13.
Silvestrini R, Veneroni S, Benini E, Daidone MG, Luisi A, Leutner M, Maucione A, Kenda R, Zucali R, Veronesi U: Expression of p53, glutathione S-transferase-pi, and Bcl-2 proteins and benefit from adjuvant radiotherapy in breast cancer. J Natl Cancer Inst. 1997, 89: 639-645. 10.1093/jnci/89.9.639.CrossRefPubMed
14.
Huang J, Tan PH, Thiyagarajan J, Bay BH: Prognostic significance of glutathione S-transferase-pi in invasive breast cancer. Mod Pathol. 2003, 16: 558-565. 10.1097/01.MP.0000071842.83169.5A.CrossRefPubMed
15.
Shami PJ, Saavedra JE, Wang LY, Bonifant CL, Diwan BA, Singh SV, Gu Y, Fox SD, Buzard GS, Citro ML, Waterhouse DJ, Davies KM, Ji X, Keefer LK: JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity. Mol Cancer Ther. 2003, 2: 409-417.PubMed
16.
Shami PJ, Saavedra JE, Bonifant CL, Chu J, Udupi V, Malaviya S, Carr BI, Kar S, Wang M, Jia L, Jia L, Ji X, Keefer LK: Antitumor activity of JS-K [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and related O2-aryl diazeniumdiolates in vitro and in vivo. J Med Chem. 2006, 49: 4356-4366. 10.1021/jm060022h.CrossRefPubMed
17.
Ren Z, Kar S, Wang Z, Wang M, Saavedra JE, Carr BI: JS-K, a novel non-ionic diazeniumdiolate derivative, inhibits Hep 3B hepatoma cell growth and induces c-Jun phosphorylation via multiple MAP kinase pathways. J Cell Physiol. 2003, 197: 426-434. 10.1002/jcp.10380.CrossRefPubMed
18.
Udupi V, Yu M, Malaviya S, Saavedra JE, Shami PJ: JS-K, a nitric oxide prodrug, induces cytochrome c release and caspase activation in HL-60 myeloid leukemia cells. Leuk Res. 2006, 30: 1279-1283. 10.1016/j.leukres.2005.12.007.CrossRefPubMed
19.
Kiziltepe T, Hideshima T, Ishitsuka K, Ocio EM, Raje N, Catley L, Li CQ, Trudel LJ, Yasui H, Vallet S, Kutok JL, Chauhan D, Mitsiades CS, Saavedra JE, Wogan GN, Keefer LK, Shami PJ, Anderson KK: JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. Blood. 2007, 110: 709-718. 10.1182/blood-2006-10-052845.CrossRefPubMedPubMedCentral
20.
Saavedra JE, Srinivasan A, Bonifant CL, Chu J, Shanklin AP, Flippen-Anderson JL, Rice WG, Turpin JA, Davies KM, Keefer LK: The secondary amine/nitric oxide complex ion R(2)N[N(O)NO](-) as nucleophile and leaving group in S9N)Ar reactions. J Org Chem. 2001, 66: 3090-3098. 10.1021/jo0016529.CrossRefPubMed
21.
Mackay M, Gale D, Wilshire J: Structural studies of some 1-polymethyleneimino-2,4-dinitrobenzenes and related compounds; crystal structure of 1-(cis-2',6'-dimethylpiperidin-1'-yl)-2,4-dinitrobenzene. Aust J Chem. 2000, 53: 715-722. 10.1071/CH00076.CrossRef
22.
Yoneda T, Williams PJ, Hiraga T, Niewolna M, Nishimura R: A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Miner Res. 2001, 16: 1486-1495. 10.1359/jbmr.2001.16.8.1486.CrossRefPubMed
23.
Costa C, Soares R, Reis-Filho J, Leitao D, Amendoeira I, Schmitt F: Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer. J Clin Pathol. 2002, 55: 429-434.CrossRefPubMedPubMedCentral
24.
Denkert C, Winzer KJ, Muller BM, Weichert W, Pest S, Kobel M, Kristiansen G, Reles A, Siegert A, Guski H, Hauptmann S: Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer. 2003, 97: 2978-2987. 10.1002/cncr.11437.CrossRefPubMed
25.
Zhang XH, Huang DP, Guo GL, Chen GR, Zhang HX, Wan L, Chen SY: Coexpression of VEGF-C and COX-2 and its association with lymphangiogenesis in human breast cancer. BMC Cancer. 2008, 8: 4-10.1186/1471-2407-8-4.CrossRefPubMedPubMedCentral
26.
Tari AM, Simeone AM, Li YJ, Gutierrez-Puente Y, Lai S, Symmans WF: Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl)retinamide inhibitory effects in breast cancer cells. Lab Invest. 2005, 85: 1357-1367. 10.1038/labinvest.3700339.CrossRefPubMed
27.
Simeone AM, Nieves-Alicea R, McMurtry VC, Colella S, Krahe R, Tari AM: Cyclooxygenase-2 uses the protein kinase C/interleukin-8/urokinase-type plasminogen activator pathway to increase the invasiveness of breast cancer cells. Int J Oncol. 2007, 30: 785-792.PubMed
28.
Simeone A-M, Colella S, Krahe R, Johnson MM, Mora E, Tari AM: N-(4-Hydroxyphenyl)retinamide and nitric oxide pro-drugs exhibit apoptotic and anti-invasive effects against bone metastatic breast cancer cells. Carcinogenesis. 2006, 27: 568-577. 10.1093/carcin/bgi233.CrossRefPubMed
29.
Hendrix MJ, Seftor EA, Seftor RE, Fidler IJ: A simple quantitative assay for studying the invasive potential of high and low human metastatic variants. Cancer Lett. 1987, 38: 137-147. 10.1016/0304-3835(87)90209-6.CrossRefPubMed
30.
Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM, McEwan RN: A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 1987, 47: 3239-3245.PubMed
31.
Terranova VP, Hujanen ES, Loeb DM, Martin GR, Thornburg L, Glushko V: Use of a reconstituted basement membrane to measure cell invasiveness and select for highly invasive tumor cells. Proc Natl Acad Sci USA. 1986, 83: 465-469. 10.1073/pnas.83.2.465.CrossRefPubMedPubMedCentral
32.
Coleman RE: Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006, 12: 6243s-6249s. 10.1158/1078-0432.CCR-06-0931.CrossRefPubMed
33.
Buckwalter JA, Glimcher MJ, Cooper RR, Recker R: Bone biology. I: structure, blood supply, cells, matrix, and mineralization. Instr Course Lect. 1996, 45: 371-386.PubMed
34.
Hall CL, Dai J, van Golen KL, Keller ET, Long MW: Type I collagen receptor (alpha 2 beta 1) signaling promotes the growth of human prostate cancer cells within the bone. Cancer Res. 2006, 66: 8648-8654. 10.1158/0008-5472.CAN-06-1544.CrossRefPubMed
35.
Nabha SM, dos Santos EB, Yamamoto HA, Belizi A, Dong Z, Meng H, Saliganan A, Sabbota A, Bonfil RD, Cher ML: Bone marrow stromal cells enhance prostate cancer cell invasion through type I collagen in an MMP-12 dependent manner. Int J Cancer. 2008, 122: 2482-2490. 10.1002/ijc.23431.CrossRefPubMed
36.
Park MJ, Park IC, Hur JH, Kim MS, Lee HC, Woo SH, Lee KH, Rhee CH, Hong SI, Lee SH: Modulation of phorbol ester-induced regulation of matrix metalloproteinases and tissue inhibitors of metalloproteinases by SB20 a specific inhibitor of p38 mitogen-activated protein kinase. J Neurosurg. 3580, 97: 112-118.CrossRef
37.
Horiuchi H, Kawamata H, Furihata T, Omotehara F, Hori H, Shinagawa Y, Ohkura Y, Tachibana M, Yamazaki T, Ajiki T, Kuroda Y, Fujimori T: A MEK inhibitor (U0126) markedly inhibits direct liver invasion of orthotopically inoculated human gallbladder cancer cells in nude mice. J Exp Clin Cancer Res. 2004, 23: 599-606.PubMed
38.
Munshi HG, Wu YI, Mukhopadhyay S, Ottaviano AJ, Sassano A, Koblinski JE, Platanias LC, Stack MS: Differential regulation of membrane type 1-matrix metalloproteinase activity by ERK 1/2- and p38 MAPK-modulated tissue inhibitor of metalloproteinases 2 expression controls transforming growth factor-beta1-induced pericellular collagenolysis. J Biol Chem. 2004, 279: 39042-39050. 10.1074/jbc.M404958200.CrossRefPubMed
39.
Hirai Y, Migita K, Honda S, Ueki Y, Yamasaki S, Urayama S, Kamachi M, Kawakami A, Ida H, Kita M, Fukuda T, Shibatomi K, Kawabe A, Aoyagi T, Eguchi K: Effects of nitric oxide on matrix metalloproteinase-2 production by rheumatoid synovial cells. Life Sci. 2001, 68: 913-920. 10.1016/S0024-3205(00)00998-X.CrossRefPubMed
40.
Jurasz P, Sawicki G, Duszyk M, Sawicka J, Miranda C, Mayers I, Radomski MW: Matrix metalloproteinase 2 in tumor cell-induced platelet aggregation: regulation by nitric oxide. Cancer Res. 2001, 61: 376-382.PubMed
41.
Ahn SM, Jeong SJ, Kim YS, Sohn Y, Moon A: Retroviral delivery of TIMP-2 inhibits H-ras-induced migration and invasion in MCF10A human breast epithelial cells. Cancer Lett. 2004, 207: 49-57. 10.1016/j.canlet.2003.11.025.CrossRefPubMed
42.
Yoneda T, Sasaki A, Dunstan C, Williams PJ, Bauss F, De Clerck YA, Mundy GR: Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate ibandronate and tissue inhibitor of the matrix metalloproteinase-2. J Clin Invest. 1997, 99: 2509-2517. 10.1172/JCI119435.CrossRefPubMedPubMedCentral
43.
Sacco MG, Soldati S, Indraccolo S, Cato EM, Cattaneo L, Scanziani E, Vezzoni P: Combined antiestrogen, antiangiogenic and anti-invasion therapy inhibits primary and metastatic tumor growth in the MMTVneu model of breast cancer. Gene Ther. 2003, 10: 1903-1909. 10.1038/sj.gt.3302082.CrossRefPubMed
44.
Ree AH, Florenes VA, Berg JP, Maelandsmo GM, Nesland JM, Fodstad O: High levels of messenger RNAs for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastases. Clin Cancer Res. 1997, 3: 1623-1628.PubMed
45.
Vizoso FJ, Gonzalez LO, Corte MD, Rodriguez JC, Vazquez J, Lamelas ML, Junquera S, Merino AM, Garcia-Muniz JL: Study of matrix metalloproteinases and their inhibitors in breast cancer. Br J Cancer. 2007, 96: 903-911. 10.1038/sj.bjc.6603666.CrossRefPubMedPubMedCentral
Metadata
Title
TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cells
Authors
Ann-Marie Simeone
Vanity McMurtry
René Nieves-Alicea
Joseph E Saavedra
Larry K Keefer
Marcella M Johnson
Ana M Tari
Publication date
01-06-2008
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2008
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2095

Other articles of this Issue 3/2008

Breast Cancer Research 3/2008 Go to the issue

Review

Alternative splicing and the progesterone receptor in breast cancer

Research article

PMC42, a breast progenitor cancer cell line, has normal-like mRNA and microRNA transcriptomes

Research article

Jab1 is a target of EGFR signaling in ERα-negative breast cancer

Research article

Breast cancer tumor growth estimated through mammography screening data

Letter

The future of mammary stem cell biology: the power of in vivo transplants

Research article

Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort
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