Abstract
Flavonoids belong to the class of plant polyphenolic compounds with over 6,000 individual structures known. These phytochemicals have attracted the interest of the scientists, because they possess a remarkable spectrum of biological activities, such as antiallergic, antiinflammatory, antioxidant, antimutagenic and anticarcinogenic. In this work, we compared the anticancer potential of two flavonoids, quercetin and pelargonidin, on highly metastatic B16-F10 melanoma murine cells. We have evaluated different parameters related to cell proliferation and differentiation, such as cell number, toxicity, intracellular content of polyamines and transglutaminase (TG, EC 2.3.2.13) activity. The higher inhibition of tumor cell growth, with respect to control, was obtained with quercetin cell treatment, i.e. 32% reduction after 48 h and 39% reduction after 72 h of incubation (P < 0.001). In parallel, quercetin-treated cells showed a similar decrease in polyamine content. TG activity was fourfold increased, with respect to control, after 48 h and twofold increased after 72 h (P < 0.001). Pelargonidin treatment did not show significant antiproliferative effects and any increase in TG activity. Proteomic approach was used to investigate changes in protein expression profiles in tumor cells following quercetin treatment. Changes in expression of 60 proteins were detected, i.e. 8 proteins were down-regulated, 35 up-regulated, 11 “de novo” synthetized proteins and 6 suppressed proteins were present in treated cells. A 80 kDa spot, identified as TG type 2 by Western blot analysis, presented a fourfold increase in intensity, confirming the key role played by TG in the induction of cancer cell differentiation.
Similar content being viewed by others
References
Arani I, Adler-Storthz K, Chen Z, Tyring SK, Brysk H, Brysk MM (1997) Differentiation markers in oral carcinoma cell lines and tumors. Anticancer Res 17:4607–4610
Atalay M, Gordillo G, Roy S, Rovin B, Bagchi D, Bagchi M, Sen CK (2003) Antiangiogenic property of edible berry in a model of hemangioma. FEBS Lett 44(1–3):252–257
Autuori F, Farrace MG, Oliverio S, Piredda L, Piacentini M (1998) ‘‘Tissue’’ transglutaminase and apoptosis. Adv Biochem Eng Biotechnol 62:129–136
Avila MA, Velasco JA, Cansado J, Notario V (1994) Quercetin mediates the down-regulation of mutant p53 in the human breast cancer cell line MDA-MB468. Cancer Res 54:2424–2428
Bagchi D, Garg A, Krohn RL, Bagchi M, Tran MX, Stohs SJ (1997) Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Res Commun Mol Pathol Pharmacol 95(2):179–189
Benedetti L, Grignani F, Scicchitano BM, Jetten AM, Diverio D, Lococo F, Avisati G, Gambacorti-Passerini C, Adamo S, Levin AA, Pelicci PG, Nervi C (1996) Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RAalpha-mediated increase of type II transglutaminase. Blood 87:1939–1950
Beninati S (1995) Post-translational modification of protein in cancer cells: the transglutaminase-catalyzed reactions. Cancer J 8:234–236
Beninati S (1997) Transglutaminase activity and protein polyamine binding capacity in animal and plant cells. In: Pandalai G (ed) Recent developments in phytochemistry, vol 1. Res Signpost, Kerala, pp 243–253
Beninati S, Abbruzzese A, Cardinali M (1993) Differences in thepost-translational modification of proteins by polyamines between weakly and highly metastatic B16 melanoma cells. Int J Cancer 53:792–797
Beninati S, Martinet N, Folk JE (1988) High-performance liquid chromatographic method for the determination of ε-(γ-glutamyl)lysine and mono- and bis-γ-glutamylderivatives of putrescine and spermidine. J Chromatogr 443:329–335
Beninati S, Piacentini M (2004) The transglutaminase family: an overview. Amino Acids 26:367–372
Beninati S, Senger DR, Cordella Miele E, Mukhrjee AB, Singh K, Mukherjee BB (1994) Osteopontin: its transglutaminase-catalyzed postranslational modifications and cross-linking to fibronectin. J Biochem 115:675–682
Bomser J, Madhavi DL, Singletary K, Smith MA (1996) In vitro anticancer activity of fruit extracts from Vaccinium species. Planta Med 62(3):212–216
Caraglia M, Marra M, Giuberti G, D’Alessandro AM, Beninati S, Lentini A et al (2002) Theophylline-induced apoptosis is paralleled by protein kinase A-dependent tissue transglutaminase activation in cancer cells. J Biochem 132:45–52
Chu YF, Sun J, Wu X, Liu RH (2002) Antioxidant and antiproliferative activities of vegetables. J Agric Food Chem 50:6910–6916
Cooper-Driver GA (2001) Contributions of Jeffrey Harborne and coworkers to the study of anthocyanins. Phytochemistry 56:229–236
Detre Z, Jellinek H, Miskulin M, Robert AM (1986) Studies on vascular permeability in hypertension: action of anthocyanosides. Clin Physiol Biochem 4(2):143–149
Dragsted LO, Strube M, Larsen JC (1993) Cancer-protective factors in fruits and vegetables: biochemical and biological background. Pharmacol Toxicol 72:116–135
Elia G, Amici C, Rossi A, Santoro MG (1996) Modulation of prostaglandin A1-induced thermotolerance by quercetin in human leukemic cells: role of heat shock protein 70. Cancer Res 56(1):210–217
Facchiano F, D’Arcangelo D, Riccomi A, Lentini A, Beninati S, Capogrossi MC (2001) Transglutaminase activity is involved in polyamine-induced programed cell death. Exp Cell Res 271:118–129
Ferry DR, Smith A, Malkhandi J, Fyfe DW, de Takats PG, Anderson D, Baker J, Kerr DJ (1996) Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2(4):659–668
Fesus L (1993) Biochemical events in naturally occurrring forms of cell death. FEBS Lett 328:1–5
Fidler IJ (1973) Selection of successive tumor cell lines for metastasis. Nature 245:148–149
Folk JE (1980) Transglutaminases. Ann Rev Biochem 49:517–531
Galati G, O’ Brien P (2004) Potential toxicity of flavonoids and other dietary phenolics: significance for their chemopreventive and anticancer properties. Free Radic Biol Med 37:287–303
Hansen RK, Oesterreich S, Lemieux P, Sarge KD, Fuqua SA (1997) Quercetin inhibits heat shock protein induction but not heat shock factor DNA-binding in human breast carcinoma cells. Biochem Biophys Res Commun 239(3):851–856
Koishi M, Hosokawa N, Sato M, Nakai A, Hirayoshi K, Hiraoka M, Abe M, Nagata K (1992) Quercetin, an inhibitor of heat shock protein synthesis, inhibits the acquisition of thermotolerance in a human colon carcinoma cell line. Jpn J Cancer Res 83(11):1216–1222
Lentini A, Abbruzzese A, Caraglia M, Marra M, Beninati S (2004) Protein-polyamine conjugation by transglutaminase in cancer cell differentiation. Amino Acids 26:331–337
Lentini A, Autuori F, Mattioli P, Caraglia M, Abbruzzese A, Beninati S (2000) Evaluation of the efficacy of potential antineoplastic drugs on tumour metastasis by a computer-assisted image analysis. Eur J Cancer 36:1572–1577
Lentini A, Beninati S (2002) Differentiation therapy of cancer: transglutaminase as diffentiative tool. Minerva Biotechnology 14:159–164
Lentini A, Forni C, Provenzano B, Beninati S (2007) Enhancement of transglutaminase activity and polyamine depletion in B16–F10 melanoma cells by flavonoids naringenin and hesperitin correlate to reduction of the in vivo metastatic potential. Amino Acids 32(1):95–100
Piantelli M, Maggiano N, Ricci R, Larocca LM, Capelli A, Scambia G, Isola G, Natali PG, Ranelletti FO (1995) Tamoxifen and quercetin interact with type II estrogen binding sites and inhibit the growth of human melanoma cells. J Invest Dermatol 105(2):248–253
Ranelletti FO, Maggiano N, Serra FG, Ricci R, Larocca LM, Lanza P, Scambia G, Fattorossi A, Capelli A, Piantelli M (2000) Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors. Int J Cancer 85(3):438–445
Sun J, Chu YF, Wu X, Liu RH (2002) Antioxidant and antiproliferative activities of fruits. J Agric Food Chem 50:7449–7454
Tabor CW, Tabor H (1976) 1, 4-Diaminobutane (putrescine), spermidine and spermine. Ann Rev Biochem 45:285–306
Thacher SM, Rice RH (1985) Keratinocyte-specific transglutaminase of cultured human epidermal cells: relation to cross-linked envelope formation and terminal differentiation. Cell 40:685–695
Thiele CJ, Gore S, Collins S, Waxman S, Miller W (2000) Differentiate or die: the view from Montreal. Cell Death Differ 7(10):1014–1017
Upchurch HF, Convay E, Patterson MK Jr, Birckbichler PJ, Maxwell MD (1987) Cellular transglutaminase has affinity for extracellular matrix. In Vitro Cell Dev Biol 23:795–800
Waladkhani AR, Clemens MR (1998) Effect of dietary phytochemicals on cancer development. Int J Mol Med 1:747–753
Wang H, Nair MG, Strasburg GM, Chang YC, Booren AM, Gray JI, DeWitt DL (1999) Antioxidant and antiinflammatory activities of anthocyanins and their aglycon, cyanidin, from tart cherries. J Nat Prod 62(2):294–306
Yoshida M, Yamamoto M, Nikaido T (1992) Quercetin arrests human leukemic T-cells in late G1 phase of the cell cycle. Cancer Res 52(23):6676–6681
Acknowledgments
This work was supported by grants from MIUR (PRIN 2004, project no. 2004067819) and from the Russian Federation (Federal Education Agency).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Forni, C., Braglia, R., Lentini, A. et al. Role of transglutaminase 2 in quercetin-induced differentiation of B16-F10 murine melanoma cells. Amino Acids 36, 731–738 (2009). https://doi.org/10.1007/s00726-008-0158-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-008-0158-y