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Transient delay of radiation-induced apoptosis by phorbol acetate

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Abstract

The mechanisms of interference of a model tumour promoter 12-O-tetra-decanoylphorbol-13-acetate (TPA) with radiation-induced apoptosis in human peripheral lymphocytes have been investigated. The cells were treated with TPA under various conditions and thereafter exposed to a single lethal dose of gamma radiation. Morphological and biochemical changes characteristic of apoptosis were followed up to 72 h of post-irradiation time. Acute exposure to low concentration of TPA resulted in delay in the onset of radiation-induced apoptosis (determined as morphological changes and rate of mitochondrial demise) by 24–48 h as compared to the irradiated, sham TPA-treated cells. The time course of this delay correlated well with confinement of the p53 protein to the cytoplasm and increase in bcl-2 levels at the nuclear periphery of irradiated cells. Our results indicate that confinement of p53 in the cytoplasm is one of the potential mechanisms by which TPA interferes with the process of radiation-induced apoptosis in human lymphocytes.

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References

  • Beham A, Marin MC, Fernandez A, Herrmann J, Brisbay S, Tari AM, Lopez-Berestein G, Lozano G, Sarkiss M, McDonnell TJ (1997) Bcl-2 inhibits p53 nuclear import following DNA damage. Oncogene 15(23):2767–2772

    Article  Google Scholar 

  • Carloni M, Meschini R, Ovidi L, Palitti F (2001) PHA-induced cell proliferation rescues human peripheral blood lymphocytes from X-ray-induced apoptosis. Mutagenesis 16(2):115–120

    Article  Google Scholar 

  • Carter S, Auer KL, Reardon DB, Birrer M, Fisher PB, Valerie K, Schmidt-Ullrich R, Mikkelsen R, Dent P (1998) Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells. Oncogene 16(21):2787–2796

    Article  Google Scholar 

  • Czene S, Testa E, Nygren J, Belyaev I, Harms-Ringdahl M (2002) DNA fragmentation and morphological changes in apoptotic human lymphocytes. Biochem Biophys Res Commun 294(4):872–878

    Article  Google Scholar 

  • Delic J, Magdelenat H, Barbaroux C, Chaillet MP, Dubray B, Gluckman E, Fourquet A, Girinsky T, Cosset JM (1995) In vivo induction of apoptosis in human lymphocytes by therapeutic fractionated total body irradiation. Br J Radiol 68(813):997–1003

    Article  Google Scholar 

  • Dyer RB, Herzog NK (1995) Isolation of intact nuclei for nuclear extract preparation from a fragile B-lymphocyte cell line. Biotechniques 19(2):192–195

    Google Scholar 

  • Evan GI, Vousden KH (2001) Proliferation, cell cycle and apoptosis in cancer. Nature 411(6835):342–348

    Article  ADS  Google Scholar 

  • Fritsche M, Haessler C, Brandner G (1993) Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene 8(2):307–318

    Google Scholar 

  • Garzotto M, White-Jones M, Jiang Y, Ehleiter D, Liao WC, Haimovitz-Friedman A, Fuks Z, Kolesnick R (1998) 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. Cancer Res 58(10):2260–2264

    Google Scholar 

  • Hendry JH, West CM (1997) Apoptosis and mitotic cell death: their relative contributions to normal-tissue and tumour radiation response. Int J Radiat Biol 71(6):709–719

    Article  Google Scholar 

  • Holmstrom TH, Chow SC, Elo I, Coffey ET, Orrenius S, Sistonen L, Eriksson JE (1998) Suppression of Fas/APO-1-mediated apoptosis by mitogen-activated kinase signaling. J Immunol 160(6):2626–2636

    Google Scholar 

  • Hong M, Lai MD, Lin YS, Lai MZ (1999) Antagonism of p53-dependent apoptosis by mitogen signals. Cancer Res 59(12):2847–2852

    Google Scholar 

  • Hrzenjak M, Shain SA (1995) Protein kinase C-dependent and -independent pathways of signal transduction in prostate cancer cells: fibroblast growth factor utilization of a protein kinase C-independent pathway. Cell Growth Differ 6(9):1129–1142

    Google Scholar 

  • Isonishi S, Ohkawa K, Tanaka T, Howell SB (2000) Depletion of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) enhances platinum drug sensitivity in human ovarian carcinoma cells. Br J Cancer 82(1):34–38

    Article  Google Scholar 

  • Liang SH, Clarke MF (2001) Regulation of p53 localization. Eur J Biochem 268(10):2779–2783

    Article  Google Scholar 

  • Meijer AE, Saeidi AB, Zelenskaya A, Czene S, Granath F, Harms-Ringdahl M (1999) Influence of dose-rate, post-irradiation incubation time and growth factors on interphase cell death by apoptosis and clonogenic survival of human peripheral lymphocytes. Int J Radiat Biol 75(10):1265–1273

    Article  Google Scholar 

  • Miyashita T, Harigai M, Hanada M, Reed JC (1994a) Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res 54(12):3131–3135

    Google Scholar 

  • Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC (1994b) Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9(6):1799–1805

    Google Scholar 

  • Miyashita T, Kitada S, Krajewski S, Horne WA, Delia D, Reed JC (1995) Overexpression of the Bcl-2 protein increases the half-life of p21Bax. J Biol Chem 270(44):26049–26052

    Article  Google Scholar 

  • Moll UM, Ostermeyer AG, Haladay R, Winkfield B, Frazier M, Zambetti G (1996) Cytoplasmic sequestration of wild-type p53 protein impairs the G1 checkpoint after DNA damage. Mol Cell Biol 16(3):1126–1137

    Article  Google Scholar 

  • Nguyen-Ba G, Vasseur P (1999) Epigenetic events during the process of cell transformation induced by carcinogens (review). Oncol Rep 6(4):925–932

    Google Scholar 

  • Ogilvy S, Metcalf D, Print CG, Bath ML, Harris AW, Adams JM (1999) Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. Proc Natl Acad Sci USA 96(26):14943–14948

    Article  ADS  Google Scholar 

  • Plas DR, Rathmell JC, Thompson CB (2002) Homeostatic control of lymphocyte survival: potential origins and implications. Nat Immunol 3(6):515–521

    Article  Google Scholar 

  • Reiners JJ Jr, Singh KP (1997) Susceptibility of 129/SvEv mice in two-stage carcinogenesis protocols to 12-O-tetradecanoylphorbol-13-acetate promotion. Carcinogenesis 18(3):593–597

    Article  Google Scholar 

  • Rincon M, Flavell RA, Davis RA (2000) The JNK and P38 MAP kinase signaling pathways in T cell-mediated immune responses. Free Radic Biol Med 28(9):1328–1337

    Article  Google Scholar 

  • Robertson JD, Orrenius S (2000) Molecular mechanisms of apoptosis induced by cytotoxic chemicals. Crit Rev Toxicol 30(5):609–627

    Article  Google Scholar 

  • Ryan JJ, Prochownik E, Gottlieb CA, Apel IJ, Merino R, Nunez G, Clarke MF (1994) c-myc and bcl-2 modulate p53 function by altering p53 subcellular trafficking during the cell cycle. Proc Natl Acad Sci USA 91(13):5878–5882

    Article  ADS  Google Scholar 

  • Schiavone N, Rosini P, Quattrone A, Donnini M, Lapucci A, Citti L, Bevilacqua A, Nicolin A, Capaccioli S (2000) A conserved AU-rich element in the 3′ untranslated region of bcl-2 mRNA is endowed with a destabilizing function that is involved in bcl-2 down-regulation during apoptosis. FASEB J 14(1):174–184

    Google Scholar 

  • Schmidt-Ullrich RK, Dent P, Grant S, Mikkelsen RB, Valerie K (2000) Signal transduction and cellular radiation responses. Radiat Res 153(3):245–257

    Article  Google Scholar 

  • Seki H, Kanegane H, Iwai K, Konno A, Ohta K, Yachie A, Taniguchi N, Miyawaki T (1994) Ionizing radiation induces apoptotic cell death in human TcR-gamma/delta+ T and natural killer cells without detectable p53 protein. Eur J Immunol 24(11):2914–2917

    Article  Google Scholar 

  • Shaulsky G, Goldfinger N, Ben-Ze’ev A, Rotter V (1990) Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol 10(12):6565–6577

    Article  Google Scholar 

  • Shen SC, Huang TS, Jee SH, Kuo ML (1998) Taxol-induced p34cdc2 kinase activation and apoptosis inhibited by 12-O- tetradecanoylphorbol-13-acetate in human breast MCF-7 carcinoma cells. Cell Growth Differ 9(1):23–29

    Google Scholar 

  • Shonai T, Adachi M, Sakata K, Takekawa M, Endo T, Imai K, Hareyama M (2002) MEK/ERK pathway protects ionizing radiation-induced loss of mitochondrial membrane potential and cell death in lymphocytic leukemia cells. Cell Death Differ 9(9):963–971

    Article  Google Scholar 

  • Sordet O, Bettaieb A, Bruey JM, Eymin B, Droin N, Ivarsson M, Garrido C, Solary E (1999) Selective inhibition of apoptosis by TPA-induced differentiation of U937 leukemic cells. Cell Death Differ 6(4):351–361

    Article  Google Scholar 

  • Sugano T, Nitta M, Ohmori H, Yamaizumi M (1995) Nuclear accumulation of p53 in normal human fibroblasts is induced by various cellular stresses which evoke the heat shock response, independently of the cell cycle. Jpn J Cancer Res 86(5):415–418

    Article  Google Scholar 

  • Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267(5203):1456–1462

    Article  ADS  Google Scholar 

  • Wright SC, Zhong J, Zheng H, Larrick JW (1993) Nicotine inhibition of apoptosis suggests a role in tumor promotion. FASEB J 7(11):1045–1051

    Google Scholar 

Download references

Acknowledgments

This study was financially supported by grants from: European Community, Contract Number FIGH-CT1999-00011, Swedish Radiation Protection Authority, Swedish National Board for Laboratory Animals, Swedish Fund for Research without Animal Experiments and The Swedish Cancer Society.

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Authors and Affiliations

  1. Department of Molecular Biosciences, Centre for Radiation Protection Research, The Wenner-Gren Institute, Stockholm University, 106 91, Stockholm, Sweden

    Gunilla Olsson, Stefan Czene, Siamak Haghdoost & Mats Harms-Ringdahl

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  1. Gunilla Olsson
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  2. Stefan Czene
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  3. Siamak Haghdoost
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  4. Mats Harms-Ringdahl
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Correspondence to Stefan Czene.

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Olsson, G., Czene, S., Haghdoost, S. et al. Transient delay of radiation-induced apoptosis by phorbol acetate. Radiat Environ Biophys 55, 95–102 (2016). https://doi.org/10.1007/s00411-015-0626-1

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  • DOI: https://doi.org/10.1007/s00411-015-0626-1

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