- Research Article
- Published:
High intracellular Zn2+ ions modulate the VHR, ZAP-70 and ERK activities of LNCaP prostate cancer cells
Cellular & Molecular Biology Letters volume 13, pages 375–390 (2008)
Abstract
Malignant prostate tissues have markedly reduced zinc (Zn2+) contents in comparison to non-malignant tissues. In this study, we restored a high intracellular Zn2+ level to LNCaP prostate cancer cells by culturing the cells in a growth medium supplemented with a supraphysiological concentration of Zn2+ (10 μg/ml) over 5 weeks. The intracellular Zn2+ level increased in the Zn2+-treated cells, and there was a marked increase in the presence of zincosomes, a Zn2+-specific intracellular organelle. The proliferation rate of the Zn2+-treated cells was markedly reduced. There was also a significant increase (36.6% ± 6.4%) in the total tyrosine phosphorylated proteins. Vaccinia H1-related (VHR) phosphatase, zeta chain-associated protein-70 (ZAP-70) kinase and phosphorylated extracellular signal-regulated protein kinase 1 and 2 (p-ERK 1 and 2) were also present in higher abundance. Treatment with TPEN, which chelates Zn2+, reduced the abundance of VHR phosphatase and ZAP-70 kinase, but increased the abundance of p-ERK 1. However, the TPEN treatment restored the Zn2+-treated LNCaP cell proliferation to a rate comparable to that of the non Zn2+-treated cells. These results highlight the importance of a high intracellular Zn2+ content and the VHR/ZAP-70-associated pathways in the modulation of LNCaP prostate cancer cell growth.
Abbreviations
- ERK:
-
extracellular signal-regulated protein kinase
- KAP:
-
kinase-associated phosphatase
- PTK:
-
protein tyrosine kinase
- PTP:
-
protein tyrosine phosphatase
- PTP1B:
-
protein tyrosine phosphatase 1B
- PTP1C/SHP-1:
-
protein tyrosine phosphatase 1C
- TPEN:
-
N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine
- VHR:
-
vaccinia H1-related
- ZAP-70:
-
zeta chain-associated protein-70
References
Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J. and Thun, M.J. Cancer statistics, 2007. CA. Cancer J. Clin. 57 (2007) 43–66.
Deutsch, E., Maggiorella, L., Eschwege, P., Bourhis, J., Soria, J.C. and Abdulkarim, B. Environmental, genetic, and molecular features of prostate cancer. Lancet Oncol. 5 (2004) 303–313.
Zaichick, VYe., Sviridova, T.V. and Zaichick, S.V. Zinc in the human prostate gland: normal, hyperplastic and cancerous. Int. Urol. Nephrol. 29 (1997) 565–574.
Feng, P., Li, T.L., Guan, Z.X., Franklin, R.B. and Costello, L.C. Direct effect of zinc on mitochondrial apoptogenesis in prostate cells. Prostate 52 (2002) 311–318.
Feng, P., Liang, J.Y., Li, T.L., Guan, Z.X., Zou, J., Franklin, R. and Costello, L.C. Zinc induces mitochondria apoptogenesis in prostate cells. Mol. Urol. 4 (2000) 31–36.
Uzzo, R.G., Crispen, P.L., Golovine, K., Makhov, P., Horwitz, E.M. and Kolenko, V.M. Diverse effects of zinc on NF-κB and AP-1 transcription factors: implications for prostate cancer progression. Carcinogenesis 27 (2006) 1980–1990.
Ishii, K., Usui, S., Sugimura, Y., Yamamoto, H., Yoshikawa, K. and Hirano, K. Inhibition of aminopeptidase N (AP-N) and urokinase-type plasminogen activator (uPA) by zinc suppresses the invasion activity in human urological cancer cells. Biol. Pharm. Bull. 24 (2001) 226–230.
Nemoto, K., Kondo, Y., Himeno, S., Suzuki, Y., Hara, S., Akimoto, M. and Imura, N. Modulation of telomerase activity by zinc in human prostatic and renal cancer cells. Biochem. Pharmacol. 59 (2000) 401–405.
Boissier, S., Ferreras, M., Peyruchaud, O., Magnetto, S., Ebetino, F.H., Colombel, M., Delmas, P., Delaisse, J.M. and Clezardin, P. Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 60 (2000) 2949–2954.
Beyersmann, D. and Haase, H. Functions of zinc in signaling, proliferation and differentiation of mammalian cells. BioMetals 14 (2001) 331–341.
Samet, J.M., Silbajoris, R., Wu, W. and Graves, L.M. Tyrosine phosphatases as targets in metal-induced signaling in human airway epithelial cells. Am. J. Respir. Cell. Mol. Biol. 21 (1999) 357–364.
Haase, H. and Maret, W. Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp. Cell Res. 291 (2003) 289–298.
Kim, J.H., Cho, H., Ryu, S.E. and Choi, M.U. Effects of metal ions on the activity of protein tyrosine phosphatase VHR: highly potent and reversible oxidative inactivation by Cu2+ ion. Arch. Biochem. Biophys. 382 (2000) 72–80.
Brautigan, D.L., Bornstein, P. and Gallis, B. Phosphotyrosyl-protein phosphatase. Specific inhibition by Zn. J. Biol. Chem. 256 (1981) 6519–6522.
Hansson, A. Extracellular zinc ions induces mitogen-activated protein kinase activity and protein tyrosine phosphorylation in bombesin-sensitive Swiss 3T3 fibroblasts. Arch. Biochem. Biophys. 328 (1996) 233–238.
Huang, S., Maher, V.M. and McCormick, J. Involvement of intermediary metabolites in the pathway of extracellular Ca2+-induced mitogen-activated protein kinase activation in human fibroblasts. Cell Signal 11 (1999) 263–274.
Wu, W, Graves, L.M., Jaspers, I., Devlin, R.B., Reed, W. and Samet, J.M. Activation of the EGF receptor signaling pathway in human airway epithelial cells exposed to metals. Am. J. Physiol. 277 (1999) L924–L931.
Samet, J.M., Graves, L.M., Quay, J., Dailey, L.A., Devlin, R.B., Ghio, A.J., Wu, W., Bromberg, P.A. and Reed, W. Activation of MAPKs in human bronchial epithelial cells exposed to metals. Am. J. Physiol. 275 (1998) L551–L558.
Park, J.A. and Koh, J.Y. Induction of an immediate early gene egr-1 by zinc though extracellular signal-regulated kinase activation in cortical culture: its role in zinc-induced neuronal death. J. Neurochem. 73 (1999) 450–456.
Makino, T., Saito, M., Horiguchi, D. and Kina, K. A highly sensitive colorimetric determination of serum zinc using water-soluble pyridylazo dye. Clin. Chim. Acta. 120 (1982) 127–135.
Huang, L., Kirschke, C.P. and Zhang, Y. Decreased intracellular zinc in human tumorigenic prostate epithelial cells: a possible role in prostate cancer progression. Cancer Cell Int. 6 (2006) 10, DOI: 10.1186/1475-2867-6-10.
Costello, L.C., Liu, Y., Zou, J. and Franklin, R.B. Evidence for a zinc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone. J. Biol. Chem. 274 (1999) 17499–17504.
Franklin, R.B., Ma, J., Zou, J., Guan, Z., Kukoyi, B.I., Feng, P. and Costello, L.C. Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells. J. Inorg. Biochem. 96 (2003) 435–442.
Feng, P., Li, T.L., Guan, Z.X., Franklin, R.B. and Costello, L.C. Effect of zinc on prostatic tumorigenicity in nude mice. Ann. N.Y. Acad. Sci. 1010 (2003) 316–320.
Gioeli, D., Mandell, J.W., Petroni, G.R., Frierson, H.F. Jr. and Weber, M.J. Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res. 59 (1999) 279–284.
Ross, J.S., Kallakury, B.V., Sheehan, C.E., Fisher, H.A., Kaufman, R.P. Jr., Kaur, P., Gray, K. and Stringer, B. Expression of nuclear factor-κB and IκBa proteins in prostatic adenocarcinomas: correlation of nuclear factor-κB immunoreactivity with disease recurrence. Clin. Cancer Res. 10 (2004) 2466–2472.
Mulholland, D.J., Dedhar, S., Wu, H. and Nelson, C.C. PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer. Oncogene 25 (2006) 329–337.
Park, K.S., Lee, N.G., Lee, K.H., Seo, J.T. and Choi, K.Y. The ERK pathway involves positive and negative regulations of HT-29 colorectal cancer cell growth by extracellular zinc. Am. J. Physiol. Gastrointest. Liver Physiol. 285 (2003) G1181–G1188.
Klein, C., Creach, K., Irintcheva, V., Hughes, K.J., Blackwell, P.L., Corbett, J.A., and Baldassare, J.J. Zinc induces ERK-dependent cell death through a specific Ras isoform. Apoptosis 11 (2006) 1933–1944.
Alonso, A., Rahmouni, S., Williams, S., van Stipdonk, M., Jaroszewski, L., Godzik, A., Abraham, R.T., Schoenberger, S.P. and Mustelin, T. Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nat. Immunol. 4 (2003) 44–48.
Todd, J.L., Tanner, K.G. and Denu, J.M. Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity proteintyrosine phosphatase VHR, a novel role in down-regulating the ERK pathway. J. Biol. Chem. 274 (1999) 13271–13280.
Rahmouni, S., Cerignoli, F., Alonso, A., Tsutji, T., Henkens, R., Zhu, C., Louis-dit-Sully, C., Moutschen, M., Jiang, W. and Mustelin, T. Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. Nat. Cell Biol. 8 (2006) 524–531.
Griffith, C.E., Zhang, W. and Wange, R.L. ZAP-70-dependent and-independent activation of Erk in Jurkat T cells. Differences in signaling induced by H2O2 and Cd3 cross-linking. J. Biol. Chem. 273 (1998) 10771–10776.
Pumiglia, K.M. and Decker, S.J. Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. USA 94 (1997) 448–452.
Stanciu, M., Wang, Y., Kentor, R., Burke, N., Watkins, S., Kress, G., Reynolds, I., Klann, E., Angiolieri, M.R., Johnson, J.W. and DeFranco, D.B. Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J. Biol. Chem. 275 (2000) 12200–12206.
Goulet, A.C., Chigbrow, M., Frisk, P. and Nelson, M.A. Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells. Carcinogenesis 26 (2005) 109–117.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wong, PF., Abubakar, S. High intracellular Zn2+ ions modulate the VHR, ZAP-70 and ERK activities of LNCaP prostate cancer cells. Cell Mol Biol Lett 13, 375–390 (2008). https://doi.org/10.2478/s11658-008-0009-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.2478/s11658-008-0009-6