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Spontaneous multidrug transport in human glioma cells is regulated by transforming growth factors type β

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Summary

The multidrug transporting cell membrane molecule P-glycoprotein can be spontaneously expressed in human glioma cells. Transcripts of mdr genes were detected in glial tumor cells by polymerase chain reaction and Northern blotting, expression of P-glycoprotein was analyzed by immunocytochemistry and functional activity by cytofluorometry of fluorescent probe transport. In vitro treatment of glioma cells with vincristine induced coordinate over-expression of both mdr1 and mdr3 genes associated with very high P-glycoprotein-mediated multidrug transport, resistant to the inhibitory activity of chemosensitizers like verapamil. The physiological modulators of multidrug transport are as yet unknown. We therefore initiated a screening program to analyze the effects of cytokines on multidrug transport. We observed, that transforming growth factors β1, -β2, and β1.2-but not the related bone morphogenetic protein (BMP) 2-inhibited multidrug transport. Interestingly, BMP 2 antagonized the TGF-β induced inhibition of multidrug transport.

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References

  1. Arceci RJ, Croop JM, Horwitz SB, Housman D (1988) The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Proc Natl Acad Sci USA 85: 4350–4354

    Google Scholar 

  2. Bourhis J, Benard J, Hartmann O, Boccon-Gibod L, Lemerle J, Riou G (1989) Correlation of mdr1 gene expression with chemotherapy in neuroblastoma. J Natl Cancer Inst 81: 1401–1405

    Google Scholar 

  3. Bradley G, Juranka PF, Ling V (1988) Mechanism of multidrug resistance. Biochim Biophys Acta 948: 87–128

    Google Scholar 

  4. Broxterman HJ, Pinedo HM, Kuiper CM, van der Hoeven JJM, de Lange P, Quak JJ, Scheper RJ, Keizer HG, Schuurhuis GJ, Lankelma J (1989) Immunohistochemical detection of P-glycoprotein in human tumor cells with a low degree of drug resistance. Int J Cancer 43: 340–343

    Google Scholar 

  5. Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB (1986) Internal Duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47: 381–389

    Google Scholar 

  6. Chin KV, Tanaka S, Darlington G, Pastan I, Gottesman MM (1990) Heat shock and arsenite increase expression of the multidrug resistance (mdr1) gene in human renal carcinoma cells. J Biol Chem 265: 221–226

    Google Scholar 

  7. Cordon-Cardo CJ, O'Brien P, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86: 695–698

    Google Scholar 

  8. Croop JM, Raymond M, Haber D, Devault A, Arceci RJ, Gros P, Housman DE (1989) The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol Cell Biol 9: 1346–1350

    Google Scholar 

  9. Czarnieki CW, Chiu HH, Wong GHW, McCabe SM Palladino MA (1988) Transforming growth β1, modulates the expression of class II histocompatibility antigens on human cells. J Immunol 140: 4217–4223

    Google Scholar 

  10. Dalton WS, Grogan TM, Meltzer PS, Scheper RJ, Durie BGM, Taylor CW, Miller TP, Salmon SE (1989) Drug resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy. J Clin Oncol 7: 415–424

    Google Scholar 

  11. de Bruijn MHL, Van der Bliek AM, Biedler JL, Borst P (1986) Differential amplification and disproportionate expression of five genes in three multidrug-resistant Chinese hamster lung cell lines. Mol Cell Biol 6: 4717–4722

    Google Scholar 

  12. de Martin R, Haendler B, Hofer-Warbinek R, Gaugitsch H, Wrann M, Schluesener HJ, Seifert JM, Bodmer S, Fontana A, Hofer E (1978) Complementary DNA from human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-β gene family. EMBO J 6: 3673–3677

    Google Scholar 

  13. Derynck R, Jarett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV (1985) Human transforming growth factor-β complementary DNA sequence and expression in normal and transformed cells. Nature 316: 701–705

    Google Scholar 

  14. Endicott JA, Ling V (1989) The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 58: 137–171

    Google Scholar 

  15. Fairchild CR, Ivy SP, Rushmore T, Lee G, Koo P, Goldsmith ME, Myers CE, Farber E, Cowan KH (1987) Carcinogen-induced mdr over-expression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas. Proc Natl Acad Sci USA 84: 7701–7705

    Google Scholar 

  16. Fine RL, Patel J, Chabner BA (1988) Phorbol esters induce multidrug resistance in human breast cancer cells. Proc Natl Acad Sci USA 85: 582–586

    Google Scholar 

  17. Fojo AT, Ueda K, Slalom DJ, Poplack DG, Gottesman MM, Pastan I (1987) Expression of multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 84: 265–269

    Google Scholar 

  18. Gaveriaux C, Boesch D, Boelsterli JJ, Bollinger P, Eberle MK, Hiestand P, Payne T, Traber R, Wenger R, Loor F (1989) Overcoming multidrug resistance in chinese hamster ovary cells in vitro by cyclosporin A (Sandimmune) and nonimmunosuppressive derivatives. Br J Cancer 60: 867–871

    Google Scholar 

  19. Goldberg H, Ling V, Wong PY, Skorecki K (1988) Reduced cyclosporin accumulation in multidrug-resistant cells. Biochem Biophys Res Commun 152: 552–558

    Google Scholar 

  20. Goldstein LJ, Galski H, Fojo A, Willingham M, Lai SL, Gazdar A, Pirker R, Green A, Christ W, Brodeur GM, Lieber M, Crossman J, Gottesman MM; Pastan I (1989) Expression of a multidrug resistance gene in human tumors. J Natl Cancer Inst 81: 116–126

    Google Scholar 

  21. Gosland MP, Lum BL, Sikie BI (1989) Reversal by Cefoperazone of resistance to etoposide, doxorubicin, and vinblastine in multidrug resistant human sarcoma cells. Cancer Res 49: 6901–6905

    Google Scholar 

  22. Gottesman MM, Pastan I (1988) The multidrug transporter, a double-edged sword. J Biol Chem 263: 12163–12166

    Google Scholar 

  23. Gottesman MM, Pastan I (1988) Resistance to multiple chemotherapeutic agents in human cancer cells. Trends Pharmacol Sci 9: 54–58

    Google Scholar 

  24. Gros P, Croop J, Housman D (1986) Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47: 371–380

    Google Scholar 

  25. Guild B, Mulligan RC, Gros P, Houseman D (1988) Retroviral transfer of a murine cDNA for multidrug resistance confers pleiotropic drug resistance to cells without prior drug selection. Proc Natl Acad Sci USA 85: 1595–1599

    Google Scholar 

  26. Hsu SIH, Lothstein L, Horwitz SB (1989) Differential overexpression of three mdr gene family members in multidrug-resistant J774.2 mouse cells. Evidence that distinct P-glycoprotein precursors are encoded by unique mdr genes. J Biol Chem 264: 12053–12062

    Google Scholar 

  27. Ichikawa M, Yoshimura A, Furukawa T (1990) Modulators of the human multidrug transporter, P-glycoprotein, exist in the human plasma. Biochem Biophys Res Commun 166: 74–80

    Google Scholar 

  28. Juranka PF, Zastawny RL, Ling V (1989) P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins. FASEB J 3: 2583–2592

    Google Scholar 

  29. Kemnitz J, Freund M, Dominis M, Cohnert TR, Uysal A, Georgii A (1989) Detection of cells with multidrug-resistant phenotype in myeloproliferative disorders before therapy. Hematol Pathol 3: 73–78

    Google Scholar 

  30. Kohno K, Sato SI, Takano H, Matsuo KI, Kuwano M (1989) The direct activation of human multidrug resistance gene (mdr1) by anticancer agents. Biochem Biophy Res Commun 165: 1415–1421

    Google Scholar 

  31. Lothstein L, Hsu SIH, Horwitz SB, Greenberger LM (1989) Alternate overexpression of two phosphoglycoprotein genes is associated with changes in multidrug resistance in a J774.2 cell line. J Biol Chem 264: 16054–16058

    Google Scholar 

  32. Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning. A laboratory manual. Cold Spring Harbor Laboratory. Cold Spring Harbor

    Google Scholar 

  33. Meyers MB, Merluzzi VJ, Spengler BA, Biedler JL (1986) Epidermal growth factor receptor is increased in multidrug-resistant chinese hamster and mouse tumor cells. Proc Natl Acad Sci USA 83: 5521–5525

    Google Scholar 

  34. Neyfakh AA (1988) Use of fluorescent dyes as molecular probes for the study of multidrug resistance. Exp Cell Res 174: 168–176

    Google Scholar 

  35. Roninson IB, Chin JE, Choi K, Gros P, Housman DE, Fojo A, Shen DW, Gottesman MM, Pastan I (1986) Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells. Proc Natl Acad Sci USA 83: 4538–4542

    Google Scholar 

  36. Rothenburg M, Ling V (1989) Multidrug resistance: molecular biology and clinical relevance. J Natl Cancer Inst 81: 907–910

    Google Scholar 

  37. Scheper RJ, Bulte JWM, Brakkee JGP, Quak JJ, van der Schott E, Balm AJM, Meijer CJLM, Broxterman HJ, Kuiper CM, Lankelma J, Pinedo HM (1988) Monoclonal antibody JSB-1 detects a highly conserved epitop on the P-glycoprotein associated with multidrug resistance. Int J Cancer 42: 389–394

    Google Scholar 

  38. Schluesener HJ (1991) Multidrug transport in human glioblastoma cells is inhibited by transforming growth factors type β1, -β2, and β1.2. J Neurosci Res (in press)

  39. Schluesener HJ, Myermann R β1, -β2, and β1.2 and the bone morphogenetic protein BMP 2: members of the transforming growth factor type β supergene famuily with different morphogenetic effects on rat astrocyte cultures. Autoimmunity (in press)

  40. Shen DW, Fojo A, Chin JE, Roninson IB, Richert N, Pastan I, Gottesman MM (1986) Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science 232: 643–645

    Google Scholar 

  41. Slater LM, Murray SL, Wetzel MW, Wisdom RM, DuVall EM (1982) Verapamil restoration of daunorubicin responsiveness in daunorubicin-resistant Ehrlich ascites carcinoma. J Clin Invest 70: 1131–1134

    Google Scholar 

  42. Soranzo C, Ingrosso A, Buffa M, Della Torre G, Gambetta RA, Zunino F (1989) Changes in the three-dimensional organization of LoVo cells associated with resistance to doxorubicin. Cancer Lett 48: 37–41

    Google Scholar 

  43. Tapiero H, Munk JN, Fourcade A, Lampidis TJ (1984) Cross-resistance to rhodamine 123 in Adriamycin- and Daunorubicin-resistant Friend leukemia cell variants. Cancer Res 44: 5544–5549

    Google Scholar 

  44. Thiebault F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal tissues. Proc Natl Acad Sci USA 84: 7735–7738

    Google Scholar 

  45. Thorgeirsson SS, Huber BE, Sorrell S, Fofo A, Pastan I, Gottesman MM (1987) Expression of the multidrug-resistant gene in hepatocarcinogenesis and regenerating rat liver. Science 236: 1120–1122

    Google Scholar 

  46. Ueda K, Cardarelli C, Gottesman MM, Pastan I (1988) Expression of a full length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin and vinblastine. Proc Natl Acad Sci USA 84: 3004–3008

    Google Scholar 

  47. Van der Bliek AM, Baas F, ten Houte de Lange T, Kooiman PM, van der Velde-Koerts T, Borst P (1987) The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver. EMBO J 6: 3325–3331

    Google Scholar 

  48. Van der Bliek AM, Baas F, Van der Velde-Koerts T, Biedler JL, Meyers MB, Ozols RF, Hamilton TC (1988) Genes amplified and overexpressed in human multidrug-resistant cell lines. Cancer Res 48: 5927–5932

    Google Scholar 

  49. Wang EA, Rosen V, D'Allessandro JS, Bauduy M, Cordes P, Harada T, Isarael DI, Hewick RM, Kerns KM, LaPan P, Luxenberg DP, McQuaid D, Moutsatsos IK, Nove J, Wozney JM (1990) Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci USA 87: 2220–2224

    Google Scholar 

  50. Zuber P, Kuppner MC, de Tribolet N (1989) Transforming growth factor-β2 down-regulates HLA-DR antigen expression on human malignant glioma cells. Eur J Immunol 18: 1623–1626

    Google Scholar 

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Authors and Affiliations

  1. Abteilung für Neurologie, Neuroimmunologie, Universität Würzburg, Josef-Schneider-Straße 11, W-8700, Würzburg, Federal Republic of Germany

    H. J. Schluesener

  2. Institut für Hirnforschung, Universität Tübingen, Federal Republic of Germany

    R. Meyermann

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  1. H. J. Schluesener
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Supported by a grant from the Bundesministerium für Forschung und Technologie

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Schluesener, H.J., Meyermann, R. Spontaneous multidrug transport in human glioma cells is regulated by transforming growth factors type β. Acta Neuropathol 81, 641–648 (1991). https://doi.org/10.1007/BF00296374

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  • DOI: https://doi.org/10.1007/BF00296374

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