Suppression of LFA-1 Expression by Spermine Is Associated with Enhanced Methylation of ITGAL, the LFA-1 Promoter Area

Kano, Yoshihiko; Soda, Kuniyasu; Konishi, Fumio
February 2013
PLoS ONE;Feb2013, Vol. 8 Issue 2, p1
Academic Journal
Spermine and spermidine, natural polyamines, suppress lymphocyte function-associated antigen 1 (LFA-1) expression and its associated cellular functions through mechanisms that remain unknown. Inhibition of ornithine decarboxylase, which is required for polyamine synthesis, in Jurkat cells by 3 mM D,L-alpha-difluoromethylornithine hydrochloride (DFMO) significantly decreased spermine and spermidine concentrations and was associated with decreased DNA methyltransferase (Dnmt) activity, enhanced demethylation of the LFA-1 gene (ITGAL) promoter area, and increased CD11a expression. Supplementation with extracellular spermine (500 µM) of cells pretreated with DFMO significantly increased polyamine concentrations, increased Dnmt activity, enhanced methylation of the ITGAL promoter, and decreased CD11a expression. It has been shown that changes in intracellular polyamine concentrations affect activities of -adenosyl-L-methionine-decaroboxylase, and, as a result, affect concentrations of the methyl group donor, S-adenosylmethionine (SAM), and of the competitive Dnmt inhibitor, decarboxylated SAM. Additional treatments designed to increase the amount of SAM and decrease the amount of decarboxylated SAM–such as treatment with methylglyoxal bis-guanylhydrazone (an inhibitor of S-adenosyl-L-methionine-decaroboxylase) and SAM supplementation–successfully decreased CD11a expression. Western blot analyses revealed that neither DFMO nor spermine supplementation affected the amount of active Ras-proximate-1, a member of the Ras superfamily of small GTPases and a key protein for regulation of CD11a expression. The results of this study suggest that polyamine-induced suppression of LFA-1 expression occurs via enhanced methylation of ITGAL.


Related Articles

  • Polyamine depletion induces G1 and S phase arrest in human retinoblastoma Y79 cells. Ueda, Akiko; Araie, Makoto; Kubota, Shunichiro // Cancer Cell International;2008, Vol. 8, Special section p1 

    Background: Polyamines and ornithine decarboxylase (ODC) are essential for cell proliferation. DL-α-difluoromethylornithine (DFMO), a synthetic inhibitor of ODC, induces G1 arrest through dephosphorylation of retinoblastoma protein (pRb). The effect of DFMO on cell growth of pRb deficient...

  • Polyamines and Carcinogenesis. Bachrach, Uriel // Acta Facultatis Medicae Naissensis;2012, Vol. 29 Issue 4, p165 

    The naturally occurring polyamines, spermine, spermidine and the diamine putrescine are widespread in nature. They have been implicated in growth and differentiation processes. In 1967, we reported that cancer cells are rich in polyamines. Subsequently, it has been shown that polyamines are...

  • Differential expression of ornithine decarboxylase antizyme inhibitors and antizymes in rodent tissues and human cell lines. Ramos-Molina, Bruno; López-Contreras, Andrés; Cremades, Asunción; Peñafiel, Rafael // Amino Acids;Feb2012, Vol. 42 Issue 2/3, p539 

    Ornithine decarboxylase antizyme inhibitors, AZIN1 and AZIN2, are regulators and homologous proteins of ornithine decarboxylase (ODC), the rate limiting enzyme in the biosynthesis of polyamines. In this study, we have examined by means of real-time RT-PCR the relative abundance of mRNA of the...

  • Low-Dose Diflouromethylornithine and Polyamine Levels in Human Prostate Tissue. Messing, Edward M.; Love, Richard R. // JNCI: Journal of the National Cancer Institute;08/18/99, Vol. 91 Issue 16, p1416 

    Features a study on the effects of difluoromethylornithine on human peripheral zone prostatic ornithine decarboxylate activities and polyamine levels in patients undergoing open prostatic surgery. Measurement of testosterone, prostate-specific antigen, and prostatic acid phosphatase levels;...

  • Knockdown of ornithine decarboxylase antizyme 1 causes loss of uptake regulation leading to increased N, N-bis(ethyl)norspermine (BENSpm) accumulation and toxicity in NCI H157 lung cancer cells. Fraser, Alison; Goodwin, Andrew; Hacker-Prietz, Amy; Sugar, Elizabeth; Woster, Patrick; Casero, Robert // Amino Acids;Feb2012, Vol. 42 Issue 2/3, p529 

    Ornithine decarboxylase antizyme 1 (AZ1) is a major regulatory protein responsible for the regulation and degradation of ornithine decarboxylase (ODC). To better understand the role of AZ1 in polyamine metabolism and in modulating the response to anticancer polyamine analogues, a small...

  • The Role of Polyamines in Human Cancer: Prospects for Drug Combination Therapies. Bachmann, Andr� S. // Hawaii Medical Journal;Dec2004, Vol. 63 Issue 12, p371 

    Ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) are two key enzymes in polyamine (PA) biosynthesis and their inhibition leads to PA pool depletion and cell growth arrest. DFMO and SAM486A are specific inhibitors of ODC and AdoMetDC, respectively, and are the only...

  • Polyamine Metabolism in Isoproterenol-stimulated Mouse Salivary Glands. NELSON, NORMAN F.; BIRGITTA BROWN, K.; DOUTHIT, DOUGLAS D.; GHATAN, SINA; BROWN, DAVID G. // Journal of Dental Research;Jun1979, Vol. 58 Issue 6, p1644 

    Isoproterenol (0.3 μmole/gm body weight) was injected intraperitoneally every 24 h for three days. The synthesis of deoxyribonucleic acid, the concentration of putrescine, spermidine and spermine and the activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase were...

  • Glucocorticoids and Polyamine Inhibitors Synergize to Kill Human Leukemic CEM Cells. Miller, Aaron L.; Johnson, Betty H.; Medh, Rheem D.; Townsend, Courtney M.; Thompson, E. Brad // Neoplasia;Jan/Feb2002, Vol. 4 Issue 1, p68 

    Focuses on the ability of polyamine inhibitors to influence glucocorticoid-induced apoptosis in human lymphoblastic leukemic CEM cells. Effect of synthetic glucocorticoid dexamethasone on ornithine decarboxylase activity, mRNA and protein in CEM cells; Extent and onset of apoptotic cell death...

  • Ornithine Decarboxylase Antizyme Induces Hypomethylation of Genome DNA and Histone H3 Lysine 9 Dimethylation (H3K9me2) in Human Oral Cancer Cell Line. Yamamoto, Daisuke; Shima, Kaori; Matsuo, Kou; Nishioka, Takashi; Chang Yan Chen; Guo-fu Hu; Sasaki, Akira; Tsuji, Takanori // PLoS ONE;2010, Vol. 5 Issue 9, p1 

    Background: Methylation of CpG islands of genome DNA and lysine residues of histone H3 and H4 tails regulates gene transcription. Inhibition of polyamine synthesis by ornithine decarboxylase antizyme-1 (OAZ) in human oral cancer cell line resulted in accumulation of decarboxylated...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics