Abstract
To establish a system to study differentiation therapy drugs, we used the androgen-independent human prostate PC-3 tumor cell line as a target and α- and γ-tocopherol as inducers. Effects of α- and γ-tocopherol on the cell cycle, proliferation and differentiation, were examined. A more significant growth inhibition activity for γ- than for α-tocopherol was observed. Flow cytometry analysis of α- and γ-tocopherol-treated prostate carcinoma PC3 cells showed decreased progression into the S-phase. This effect, particularly evident for γ-tocopherol, was associated with an up-regulation and increased activity of transglutaminase 2 (TG2), a reduced DNA synthesis and a remarkable decreased levels of cyclin D1 and cyclin E. Activation of TG2 suggests that γ-tocopherol has an evident differentiative capacity on PC3 cells, leading to an increased expression of TG2, and reduced cyclin D1 and cyclin E levels, affecting cell cycle progression. It is feasible that up-regulation and activation of TG2, associated with a reduced proliferation, are parts of a large-scale reprogramming that can attenuate the malignant phenotype of PC3 cells in vitro. These data suggest further investigation on the potential use of this γ-form of vitamin E as a differentiative agent, in combination with the common cytotoxic treatments for prostate cancer therapy.
Similar content being viewed by others
References
Beninati S, Bergamini CM, Piacentini M (2009) An overview of the first 50 years of transglutaminase research. Amino Acids 36(4):591–598
Bieri JG, Evarts RP (1974) γ-Tocopherol: metabolism, biological activity and significance in human vitamin E nutrition. Am J Clin Nutr 27:980–986
Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254
Brigelius-Flohé R, Galli F (2010) Vitamin E: a vitamin still awaiting the detection of its biological function. Mol Nutr Food Res 54(5):583–587
Conte C, Floridi A, Aisa C, Piroddi M, Floridi A, Galli F (2004) Gamma-tocotrienol metabolism and antiproliferative effect in prostate cancer cells. Ann N Y Acad Sci 1031:391–394
Cooney RV, Franke AA, Harwood PJ, Hatch-Pigott V, Custer LJ, Mordan LJ (1993) γ-Tocopherol detoxification of nitrogen dioxide: superiority to α-tocopherol. Proc Natl Acad Sci USA 90:1771–1775
Dyson N (1998) The regulation of E2F by pRB-family proteins. Genes Dev 12:2245–2262
Ellerhorst J, Nguyen T, Cooper DN, Estrov Y, Lotan D, Lotan R (1999) Induction of differentiation and apoptosis in the prostate cancer cell line LNCaP by sodium butyrate and galectin-1. Int J Oncol 14:225–232
Folk JE, Chung SI (1985) Transglutaminases. Methods Enzymol 113:358–375
Galli F, Stabile AM, Betti M, Conte C, Pistilli A, Rende M, Floridi A, Azzi A (2004) The effect of alpha- and gamma-tocopherol and their carboxyethyl hydroxychroman metabolites on prostate cancer cell proliferation. Arch Biochem Biophys 423(1):97–102
Gismondi A, Lentini A, Tabolacci C, Provenzano B, Beninati S (2010) Transglutaminase-dependent antiproliferative and differentiative properties of nimesulide on B16-F10 mouse melanoma cells. Amino Acids 38(1):257–262
Gysin R, Azzi A, Visarius T (2002) Gamma-tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins. FASEB J. 16(14):1952–1954
James SY, Williams MA, Newland AC, Colston KW (1999) Leukemia cell differentiation: cellular and molecular interactions of retinoids and vitamin D. Gen Pharmacol 32:143–154
Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE (2005) Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA 294(1):56–65
Lentini A, Abbruzzese A, Caraglia M, Marra M, Beninati S (2004) Protein–polyamine conjugation by transglutaminase in cancer cell differentiation. Amino Acids 26(4):331–337
Lentini A, Provenzano B, Tabolacci C, Beninati S (2009) Protein–polyamine conjugates by transglutaminase 2 as potential markers for antineoplastic screening of natural compounds. Amino Acids 36(4):701–708
Leszczyniecka M, Roberts T, Dent P, Grant S, Fisher PB (2001) Differentiation therapy of human cancer: basic science and clinical applications. Pharmacol Ther 90:105–156
Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD 3rd, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz PA, Santella RM, Albanes D, Taylor PR, Probstfield JL, Jagpal TJ, Crowley JJ, Meyskens FL Jr, Baker LH, Coltman CA Jr (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301(1):39–51
Maier S, Reich E, Martin R, Bachem M, Altug V, Hautmann RE, Gschwend JE (2000) Tributyrin induces differentiation, growth arrest and apoptosis in androgen-sensitive and androgen-resistant human prostate cancer cell lines. Int J Cancer 88:245–251
Reis-Filho JS, Savage K, Lambros MBK, James M, Steele D, Jones RL et al (2006) Cyclin D1 protein overexpression and CCND1, PML, ALK, and NPM1 genes in lymphomas and AML. Clin Haematol 19:999–1009
Sachs L (1978) Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukaemia. Nature 274:535–539
Torricelli P, Ricci P, Provenzano B, Lentini A, Tabolacci C (2011) Synergic effect of α-tocopherol and naringenin in transglutaminase-induced differentiation of human prostate cancer cells. Amino Acids 41(5):1207–1214
Conflict of interest
Authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work is dedicated to Alberto Abbruzzese, who died in 2011.
Rights and permissions
About this article
Cite this article
Torricelli, P., Caraglia, M., Abbruzzese, A. et al. γ-Tocopherol inhibits human prostate cancer cell proliferation by up-regulation of transglutaminase 2 and down-regulation of cyclins. Amino Acids 44, 45–51 (2013). https://doi.org/10.1007/s00726-012-1278-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-012-1278-y