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International Journal of Hematology

, Volume 85, Issue 3, pp 231–237 | Cite as

Peroxisome Proliferator-Activated Receptor γ and Retinoic Acid Receptor Synergistically Up-Regulate the Tumor Suppressor PTEN in Human Promyeloid Leukemia Cells

  • Young-Rae Lee
  • Hong-Nu Yu
  • Eun-Mi Noh
  • Jong-Suk Kim
  • Eun-Kyung Song
  • Myung-Kwan Han
  • Byeong-Soo Kim
  • Sung-Ho Lee
  • Jinny Parkd
Article

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) and retinoic acid receptors (RARs) have been a focus in chemotherapy for human cancers. The tumor suppressor PTEN plays a pivotal role in the growth of human cancer cells. We investigated whether costimulation of PPARγ and RAR could synergistically up-regulate PTEN in human leukemia cells and consequently potentiate the inhibition of growth and cell cycle progression of these cells. We found that overexpression of PTEN with the adenoviral vector Ad/PTEN caused growth arrest at the G1 phase of the cell cycle of HL-60 cells. HL-60 cells treated with either a PPARγ ligand (ciglitazone) or a RAR ligand(all-trans retinoic acid [ATRA]) up-regulated PTEN in HL-60 cells. The 2 compounds in combination showed synergistic effects on PTEN expression at the protein and messenger RNA levels. Moreover, the combination of ciglitazone and ATRA synergistically reduced cell growth rates and cell cycle arrest at the G1 phase. Our results suggest that, PPARγ and RAR play an important role in controlling the growth of leukemia cells via the up-regulation of PTEN.

Key words

PPARγ RAR PTEN HL-60 

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References

  1. 1.
    Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia.Blood. 1998;91:3093–3102.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Rosen ED, Spiegelman BM. PPARγ: a nuclear regulator of metabolism, differentiation, and cell growth.J Biol Chem. 2001;276:37731- 37734.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Konopleva M, Andreeff M. Role of peroxisome proliferator-activated receptor-γ in hematologic malignancies.Curr Opin Hematol. 2002;9:294–302.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Koeffler HP. Peroxisome proliferator-activated receptor γ and cancers.Clin Cancer Res. 2003;9:1–9.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Szanto A, Nagy L. Retinoids potentiate peroxisome proliferator-activated receptor γ action in differentiation, gene expression, and lipid metabolic processes in developing myeloid cells.Mol Pharmacol. 2005;67:1935–1943.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Yasugi E, Horiuchi A, Uemura I, et al. Peroxisome proliferator-activated receptor γ ligands stimulate myeloid differentiation and lipogenesis in human leukemia NB4 cells.Dev Growth Differ. 2006;48:177–188.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Breitman TR, Selonick SE, Collins SJ. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid.Proc Natl Acad Sci U S A. 1980;77:2936–2940.CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Hirase N, Yanase T, Mu Y, et al. Thiazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60.Oncology. 1999;57(suppl 2):17–26.CrossRefGoogle Scholar
  9. 9.
    Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function.Proc Natl Acad Sci U S A. 1998;95:13513–13518.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Wen S, Stolarov J, Myers MP, et al. PTEN controls tumor-induced angiogenesis.Proc Natl Acad Sci U S A.2001;98:4622–4627.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Kim JS, Peng X, De PK, Geahlen RL, Durden DL. PTEN controls immunoreceptor (immunoreceptor tyrosine-based activation motif) signaling and the activation of Rac.Blood. 2002;99:694–697.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH.Tumor suppressor and anti-inflammatory actions of PPARγ agonists are mediated via upregulation of PTEN.Curr Biol. 2001;11:764–768.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Kim KY, Kim SS, Cheon HG. Differential anti-proliferative actions of peroxisome proliferator-activated receptor-γ agonists in MCF-7 breast cancer cells.Biochem Pharmacol. 2006;72:530–540.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Kwak YG, Song CH, Yi HK, et al. Involvement of PTEN in airway hyperresponsiveness and inflammation in bronchial asthma.J Clin Invest. 2003;111:1083–1092.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Hwang PH, Yi HK, Kim DS, Nam SY, Kim JS, Lee DY Suppression of tumorigenicity and metastasis in B16F10 cells by PTEN/MMAC1/TEP1 gene.Cancer Lett. 2001;172:83–91.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Cappellini A, Tabellini G, Zweyer M, et al. The phosphoinositide 3-kinase/Akt pathway regulates cell cycle progression of HL60 human leukemia cells through cytoplasmic relocalization of the cyclin-dependent kinase inhibitor p27Kip1 and control of cyclin D1 expression.Leukemia. 2003;17:2157–2167.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Seminario MC, Precht P, Wersto RP, Gorospe M, Wange RL. PTEN expression in PTEN-null leukaemic T cell lines leads to reduced proliferation via slowed cell cycle progression.Oncogene. 2003;22:8195–8204.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Moon SK, Kim HM, Kim CH. PTEN induces G1 cell cycle arrest and inhibits MMP-9 expression via the regulation of NF-κB and AP-1 in vascular smooth muscle cells.Arch Biochem Biophys. 2004;421:267–276.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Weng LP, Smith WM, Dahia PL, et al. PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death.Cancer Res. 1999;59:5808–5814.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Weng LP, Gimm O, Kum JB, et al. Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death.Hum Mol Genet. 2001;10:251–258.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Davies MA, Lu Y, Sano T, et al. Adenoviral transgene expression ofMMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis.Cancer Res. 1998;58:5285–5290.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Davies MA, Koul D, Dhesi H, et al. Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN.Cancer Res. 1999;59:2551–2556.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Hisatake J, O’Kelly J, Uskokovic MR, Tomoyasu S, Koeffler HP. Novel vitamin D3 analog, 21-(3-methyl-3-hydroxy-butyl)-19-nor D3, that modulates cell growth, differentiation, apoptosis, cell cycle, and induction of PTEN in leukemic cells.Blood. 2001;97:2427–2433.CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Lee YR, Shim HJ, Yu HN, et al. Dimethylsulfoxide induces upregulation of tumor suppressor protein PTEN through nuclear factor-κB activation in HL-60 cells.Leuk Res. 2005;29:401–405.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2007

Authors and Affiliations

  • Young-Rae Lee
    • 1
  • Hong-Nu Yu
    • 1
  • Eun-Mi Noh
    • 1
  • Jong-Suk Kim
    • 1
  • Eun-Kyung Song
    • 1
  • Myung-Kwan Han
    • 2
  • Byeong-Soo Kim
    • 3
  • Sung-Ho Lee
    • 3
  • Jinny Parkd
    • 4
  1. 1.Department of BiochemistryChonbuk National University Medical SchoolJeonjuKorea
  2. 2.Department of Microbiology & ImmunologyChonbuk National University Medical SchoolJeonjuKorea
  3. 3.Department of Companion and Laboratory Animal ScienceKongju National UniversityYesanKorea
  4. 4.Division of Hematology/OncologyGachon University Medical CenterInchonKorea

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