Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in degradation of extracellular matrix, a process that initiates uncontrolled spread of proliferating cancer cells and therefore plays a crucial role in cancer invasion and metastasis. Compounds able to modulate MMP activity may become important tools in cancer research. In the present study we examined the effect of two μ-selective opioids, morphine and endomorphin-2 (EM-2) on the production of MMP-2 and MMP-9 in MCF-7 cells. We report that both opioids time- and concentration-dependently inhibited the expression and secretion of these MMPs. The observed effect was not reversed by naloxone (Nal). Further experiments showed that morphine and EM-2 decreased endothelial nitric oxide synthase (eNOS) mRNA level and nitric oxide (NO) secretion in MCF-7 cells. These findings indicate that attenuation of MMP secretion by opioids was not mediated by opioid receptors but was under the control of nitric oxide system.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Engbring JA, Kleinman HK (2003) The basement membrane matrix in malignancy. J Pathol 200:465–470
Wideł MS, Wideł M (2006) Mechanisms of metastasis and molecular markers of malignant tumor progression. I. Colorectal cancer. Postepy Hig Med Dosw 60:453–470
Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S (1980) Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 284:67–68
Śliwowska I, Kopczyński Z (2005) Matrix metalloproteinases–biochemical characteristics and clinical value determination in breast cancer patients. Contemp Oncol 9:327–335
Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM (2004) Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clin Cancer Res 10:7621–7628
Lynch CC, Matrisian LM (2002) Matrix metalloproteinases in tumor-host cell communication. Differentiation 70:561–573
Ramnath N, Creaven PJ (2004) Matrix metalloproteinase inhibitors. Curr Oncol Rep 6:96–102
Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T (2003) Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 253:269–285
Mook OR, Frederiks WM, Van Noorden CJ (2004) The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta 1705:69–89
Fichna J, do-Rego JC, Chung NN, Lemieux C, Schiller PW, Poels J, Broeck JV, Costentin J, Janecka A (2007) Synthesis and characterization of potent and selective mu-opioid receptor antagonists, [Dmt(1), d-2-Nal(4)]endomorphin-1 (Antanal-1) and [Dmt(1), d-2-Nal(4)]endomorphin-2 (Antanal-2). J Med Chem 50:512–520
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159
Winer J, Jung CK, Shackel I, Williams PM (1999) Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem 270:41–49
Hatzoglou A, Kampa M, Castanas E (2005) Opioid-somatostatin interactions in regulating cancer cell growth. Front Biosci 10:244–256
Kampa M, Bakogeorgou E, Hatzoglou A, Damianaki A, Martin PM, Castanas E (1997) Opioid alkaloids and casomorphin peptides decrease the proliferation of prostatic cancer cell lines (LNCaP, PC3 and DU145) through a partial interaction with opioid receptors. Eur J Pharmacol 335:255–265
Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012
Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB (1998) The multifaceted roles of nitric oxide in cancer. Carcinogenesis 19:711–721
Pfeilschifter J, Eberhardt W, Huwiler A (2001) Nitric oxide and mechanisms of redox signalling: matrix and matrix-metabolizing enzymes as prime nitric oxide targets. Eur J Pharmacol 429:279–286
Novaro V, Pustovrh C, Colman-Lerner A, Radisky D, Lo Nostro F, Paz D, Jawerbaum A, González E (2002) Nitric oxide induces gelatinase A (matrix metalloproteinase 2) during rat embryo implantation. Fertil Steril 78:1278–1287
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 Y, Aoyagi T, Eguchi K (2001) Effects of nitric oxide on matrix metalloproteinase-2 production by rheumatoid synovial cells. Life Sci 68:913–920
Kampa M, Hatzoglou A, Notas G, Niniraki M, Kouroumalis E, Castanas E (2001) Opioids are non-competitive inhibitors of nitric oxide synthase in T47D human breast cancer cells. Cell Death Differ 8:943–952
Harimaya Y, Koizumi K, Andoh T, Nojima H, Kuraishi Y, Saiki I (2002) Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26-L5 carcinoma cells. Cancer Lett 187:121–127
Shariftabrizi A, Nifli AP, Ansari M, Saadat F, Ebrahimkhani MR, Alizadeh N, Nasseh A, Alexaki VI, Dehpour AR, Castanas E, Khorramizadeh MR (2006) Matrix metalloproteinase 2 secretion in WEHI 164 fibrosarcoma cells is nitric oxide-related and modified by morphine. Eur J Pharmacol 530:33–39
Gach K, Piestrzeniewicz M, Fichna J, Stefanska B, Szemraj J, Janecka A (2008) Opioid-induced regulation of mu-opioid receptor gene expression in the MCF-7 breast cancer cell line. Biochem Cell Biol 86:217–226
Acknowledgements
This work was supported by the grants from Polish Ministry of Science (No NN 401 0155 36) and the Medical University of Lodz (No 503-1156-2). The authors wish to thank Jozef Cieslak for his excellent technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gach, K., Szemraj, J., Wyrębska, A. et al. The influence of opioids on matrix metalloproteinase-2 and -9 secretion and mRNA levels in MCF-7 breast cancer cell line. Mol Biol Rep 38, 1231–1236 (2011). https://doi.org/10.1007/s11033-010-0222-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-010-0222-z