1887

Abstract

The efficacy of the widely used chemotherapeutic drug cisplatin is limited by the occurrence of drug-resistant tumour cells. To fully exploit the potential of this drug in cancer therapy, it is imperative to understand the molecular basis of cisplatin resistance. Using an insertional mutagenesis technique in cells of , we have identified six genes which are involved in cisplatin resistance. None of these genes has been previously linked to resistance to this drug. Several of these genes encode proteins that are involved in signal transduction pathways which regulate cell death, cell proliferation or gene regulation. The resistance of these mutant strains is specific for cisplatin, since deletion of these genes does not confer resistance to other DNA-damaging agents. Significantly, the disruption of three of these genes, encoding the sphingosine-1-phosphate lyase, the RegA cAMP phosphodiesterase and a phosphatidylinositol-4-phosphate 5-kinase, also results in abnormalities in the multicellular development of this organism, although there is no change in the rate of mitotic cell growth. This study has identified previously unsuspected molecular pathways which function in the cellular response to cisplatin and are required for normal morphogenesis, and underscores the complexity of the cellular response to cisplatin. These pathways provide potential targets for modulating the response to this important drug.

Loading

Article metrics loading...

/content/journal/micro/10.1099/00221287-146-9-2219
2000-09-01
2024-11-12
Loading full text...

Full text loading...

/deliver/fulltext/micro/146/9/1462219a.html?itemId=/content/journal/micro/10.1099/00221287-146-9-2219&mimeType=html&fmt=ahah

References

  1. Agami R., Blandino G., Oren M., Shaul Y. 1999; Interaction of c-Abl and P73α and their collaboration to induce apoptosis. Nature 399:809–817 [CrossRef]
    [Google Scholar]
  2. Alexander S., Rossomando E. F. 1992; Regulation of morphogenesis in Dictyostelium discoideum. In Morphogenesis: An Analysis of the Development of Biological Form pp. 29–61Edited by Rossomando E. F., Alexander S. New York: Marcel Dekker;
    [Google Scholar]
  3. Andrews P. A., Howell S. B. 1990; Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. Cancer Cells 2:35–43
    [Google Scholar]
  4. Baldauf S. L., Doolittle W. F. 1997; Origin and evolution of the slime molds (Mycetozoa). Proc Natl Acad Sci USA 94:12007–12012 [CrossRef]
    [Google Scholar]
  5. Bear J. E., Rawls J. F., Saxe C. L. 3rd 1998; SCAR, a WASP-related protein, isolated as a suppressor of receptor defects in late Dictyostelium development. J Cell Biol 142:1325–1335 [CrossRef]
    [Google Scholar]
  6. Bronner C. E., Welker D. L., Deering R. A. 1992; Mutations affecting sensitivity of the cellular slime mold Dictyostelium discoideum to DNA-damaging agents. Mutat Res DNA Repair 274:187–200 [CrossRef]
    [Google Scholar]
  7. Byers D., Davis R. L., Kiger J. A. Jr 1981; Defect in cyclic AMP phosphodiesterase due to the dunce mutation of learning in Drosophila melanogaster. Nature 289:79–81 [CrossRef]
    [Google Scholar]
  8. Chu G. 1994; Cellular responses to cisplatin. J Biol Chem 269:787–790
    [Google Scholar]
  9. Cocucci S., Sussman M. 1970; RNA in cytoplasmic and nuclear fractions of cellular slime mold amoebas. J Cell Biol 45:399–407 [CrossRef]
    [Google Scholar]
  10. Cvijic M. E., Yang W. L., Chin K. V. 1998a; Cisplatin resistance in cyclic AMP-dependent protein kinase mutants. Pharmacol Ther 78:115–128 [CrossRef]
    [Google Scholar]
  11. Cvijic M. E., Yang W. L., Chin K. V. 1998b; Cisplatin sensitivity in cAMP-dependent protein kinase mutants of Saccharomyces cerevisiae. Anticancer Res 18:3187–3192
    [Google Scholar]
  12. Davis R. L., Kiger J. A. Jr 1981; Dunce mutants of Drosophila melanogaster: mutants defective in the cyclic AMP phosphodiesterase enzyme system. J Cell Biol 90:101–107 [CrossRef]
    [Google Scholar]
  13. Drummond J. T., Anthoney A., Brown R., Modrich P. 1996; Cisplatin and adriamycin resistance are associated with MutL alpha and mismatch repair deficiency in an ovarian tumour cell line. J Biol Chem 271:19645–19648 [CrossRef]
    [Google Scholar]
  14. Eastman A. 1986; Re-evaluation of interaction of cis-dichloro(ethylenediamine)platinum(II) with DNA. Biochemistry 25:3912–3915 [CrossRef]
    [Google Scholar]
  15. Fink D., Nebel S., Norris P. S., Baergen R. N., Wilczynski S. P., Costa M. J., Haas M., Cannistra S. A., Howell S. B. 1998; Enrichment for DNA mismatch repair-deficient cells during treatment with cisplatin. Int J Cancer 77:741–746 [CrossRef]
    [Google Scholar]
  16. Fink D., Zheng H., Nebel S.8 other authors 1997; In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer Res 57:1841–1845
    [Google Scholar]
  17. Friedberg E. C., Walker G. C., Siede W. 1995 DNA Repair and Mutagenesis Washington, DC: American Society for Microbiology;
    [Google Scholar]
  18. Garcia M. X. U., Foote C., van Es S., Devreotes P. N., Alexander S., Alexander H. 2000; Differential developmental expression and cell type specificity of Dictyostelium catalases and their response to oxidative stress and UV-light. Biochim Biophys Acta 1492:295–310 [CrossRef]
    [Google Scholar]
  19. Gong J., Costanzo A., Yang H., Melino G., Kaelin W. G., Levrero M., Wang J. Y. J. 1999; The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399:806–809 [CrossRef]
    [Google Scholar]
  20. Good J. R., Kuspa A. 2000; Evidence that a cell-type-specific efflux pump regulates cell differentiation in Dictyostelium. Dev Biol 220:53–61 [CrossRef]
    [Google Scholar]
  21. Katabami M., Fijita H., Haneda H., Akita H., Kuzumaki N., Miyamoto H., Kawakami Y. 1992; Reduced drug accumulation in a newly established human lung squamous-carcinoma cell line resistant to cis-diamminedichloroplatinum(II). Biochem Pharmacol 44:394–397 [CrossRef]
    [Google Scholar]
  22. Kessin R. H. 1997; The evolution of the cellular slime mold. In Dictyostelium – A Model System for Cell and Developmental Biology pp. 349–362Edited by Maeda Y., Inouye K., Takeuchi I. Tokyo: Universal Academy Press;
    [Google Scholar]
  23. von Knethen A., Lotero A., Brune B. 1998; Etoposide and cisplatin induced apoptosis in activated RAW 264.7 macrophages is attenuated by cAMP-induced gene expression. Oncogene 17:387–394 [CrossRef]
    [Google Scholar]
  24. Kohn K. W. 1999; Molecular interaction map of the mammalian cell cycle control and DNA repair systems. Mol Biol Cell 10:2703–2734 [CrossRef]
    [Google Scholar]
  25. Kuppen P. J., Schuitemaker H., van’t Veer L. J., de Bruijn E. A., van Oosterom A. T., Schrier P. I. 1988; cis-Diamminedichloroplatinum(II)-resistant sublines derived from two human ovarian tumour cell lines. Cancer Res 48:3355–3359
    [Google Scholar]
  26. Kuspa A., Loomis W. F. 1992; Tagging developmental genes in Dictyostelium by restriction enzyme-mediated integration of plasmid DNA. Proc Natl Acad Sci USA 89:8803–8807 [CrossRef]
    [Google Scholar]
  27. Laurence A., Firtel R. 1999; Integration of signalling networks that regulate Dictyostelium differentiation. Annu Rev Cell Dev Biol 15:469–517 [CrossRef]
    [Google Scholar]
  28. Lee S.-K., Yu S.-L., Garcia M. X., Alexander H., Alexander S. 1997; Differential developmental expression of the repB and repD xeroderma pigmentosum related DNA helicase genes from Dictyostelium discoideum. Nucleic Acids Res 25:2365–2374 [CrossRef]
    [Google Scholar]
  29. Leon C., Vial C., Cazenave J. P., Gachet C. 1996; Cloning and sequencing of a human cDNA encoding endothelial P2Y1 purinoceptor. Gene 171:295–297 [CrossRef]
    [Google Scholar]
  30. Lippard S. J. 1982; New chemistry of an old molecule: cis-[Pt(NH3)2Cl2]. Science 218:1075–1082 [CrossRef]
    [Google Scholar]
  31. Loehrer P. J., Einhorn L. H. 1984; Cisplatin. Ann Intern Med 100:704–713 [CrossRef]
    [Google Scholar]
  32. Loijens J. C., Boronenkov I. V., Parker G. J., Anderson R. A. 1996; The phosphatidylinositol 4-phosphate 5-kinase family. Adv Enzyme Regul 36:115–140 [CrossRef]
    [Google Scholar]
  33. Loomis W. F. 1982 The Development of Dictyostelium discoideum New York: Academic Press;
    [Google Scholar]
  34. Loomis W. F. 1998; Role of PKA in the timing of developmental events in Dictyostelium cells. Microbiol Mol Biol Rev 62:684–694
    [Google Scholar]
  35. Los G., Johnson A., Yang F., Berry C., Howell S. 1998; Identification of genes differentially expressed in cisplatin-sensitive versus resistant tumour cells. In The Microarray Meeting: Technology, Application and Analysis p. 60Scottsdale, AZNature America
    [Google Scholar]
  36. Merrill A. H. J., Hunnun Y. A., Bell R. M. 1993; Introduction: sphingolipids and their metabolites in cell regulation. Adv Lipid Res 25:1–24
    [Google Scholar]
  37. Morio T., Urushihara H., Saito T.14 other authors 1998; The Dictyostelium developmental cDNA project: generation and analysis of expressed sequence tags from the first-finger stage of development. DNA Res 5:335–340 [CrossRef]
    [Google Scholar]
  38. Morowitz H. J. 1950; Absorption effects in volume irradiation of microorganisms. Science 111:229–230
    [Google Scholar]
  39. Ohndorf U. M., Rould M. A., He Q., Pabo C. O., Lippard S. J. 1999; Basis for recognition of cisplatin-modified DNA by high-mobility-group proteins. Nature 399:708–712 [CrossRef]
    [Google Scholar]
  40. Parent C. A., Devreotes P. N. 1999; A cell’s sense of direction. Science 284:765–770 [CrossRef]
    [Google Scholar]
  41. Perez R. P. 1998; Cellular and molecular determinants of cisplatin resistance. Eur J Cancer 34:1535–1542 [CrossRef]
    [Google Scholar]
  42. Podgorski G., Deering R. A. 1980; Effect of methyl methanesulfonate on survival of radiation-sensitive strains of Dictyostelium discoideum. Mutat Res 73:415–418 [CrossRef]
    [Google Scholar]
  43. Rabo Y. B., Shoshan M. C., Linder S., Hansson J. 1996; Different mechanisms are responsible for c-jun mRNA induction by cisplatin and ultraviolet light. Int J Cancer 65:821–826 [CrossRef]
    [Google Scholar]
  44. Saba J. D., Nara F., Bielawska A., Garrett S., Hannun Y. A. 1997; The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase. J Biol Chem 272:26087–26090 [CrossRef]
    [Google Scholar]
  45. Sambrook J., Fritsch E. F., Maniatis T. 1989 Molecular Cloning: a Laboratory Manual, 2nd edn. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
    [Google Scholar]
  46. Sancar A. 1999; Excision repair invades the territory of mismatch repair. Nat Genet 21:247–249 [CrossRef]
    [Google Scholar]
  47. Scagliotti G. V., Novello S., Selvaggi G. 1999; Multidrug resistance in non-small-cell lung cancer. Ann Oncol 10:S83–S86
    [Google Scholar]
  48. Shaulsky G., Escalante R., Loomis W. F. 1996; Developmental signal transduction pathways uncovered by genetic suppressors. Proc Natl Acad Sci USA 93:15260–15265 [CrossRef]
    [Google Scholar]
  49. Shaulsky G., Fuller D., Loomis W. F. 1998; A cAMP-phosphodiesterase controls PKA-dependent differentiation. Development 125:691–699
    [Google Scholar]
  50. Sherman S. E., Lippard S. J. 1987; Structural aspects of platinum anticancer drug interactions with DNA. Chem Rev 87:1153–1181 [CrossRef]
    [Google Scholar]
  51. Soll D. 1987; Methods for manipulating and investigating developmental timing in Dictyostelium discoideum. Methods Cell Biol 28:413–431
    [Google Scholar]
  52. Spiegel S. 1999; Sphingosine 1-phosphate: a prototype of a new class of second messengers. J Leukoc Biol 65:341–344
    [Google Scholar]
  53. Spudich J. 1987; Dictyostelium discoideum: molecular approaches to cell biology. Methods Cell Biol 28:1–516
    [Google Scholar]
  54. Srinivasan S., Alexander H., Alexander S. 2000; Crossing the finish line of development: regulated secretion and assembly of the Dictyostelium spore coat proteins. Trends Cell Biol 10:215–219 [CrossRef]
    [Google Scholar]
  55. Sussman M. 1987; Cultivation and synchronous morphogenesis of Dictyostelium under controlled experimental conditions. Methods Cell Biol 28:9–29
    [Google Scholar]
  56. Sutoh K. 1993; A transformation vector for Dictyostelium discoideum with a new selectable marker bsr. Plasmid 30:150–154 [CrossRef]
    [Google Scholar]
  57. Swanson R. L., Morey N. J., Doetsch P. W., Jinks-Robertson S. 1999; Overlapping specificities of base excision repair, nucleotide excision repair, recombination, and translesion synthesis pathways for DNA base damage in Saccharomyces cerevisiae. Mol Cell Biol 19:2929–2935
    [Google Scholar]
  58. Takahara P. M., Rosenzweig A. C., Frederick C. A., Lippard S. J. 1995; Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin. Nature 377:649–652 [CrossRef]
    [Google Scholar]
  59. Tam A., Nouvet F. J., Fujimura-Kamada K., Slunt H., Sisodia S. S., Michaelis S. 1998; Dual role for Ste24p in yeast a-factor maturation: NH2-terminal proteolysis and COOH-terminal CAAX processing. J Cell Biol 142:635–649 [CrossRef]
    [Google Scholar]
  60. Teicher B. A., Holden S. A., Herman T. S., Sotomayop E., Khandekar V., Rosbe K. W., Brann T. W., Korbut T. T., Frei E. III 1991; Characteristics of five human tumour cell lines and sublines resistant to cis-diamminedichloroplatinum(II). Int J Cancer 47:252–260 [CrossRef]
    [Google Scholar]
  61. Walter M. F., Kiger J. A. Jr 1984; The dunce gene of Drosophila: roles of Ca2+ and calmodulin in adenosine 3′:5′-cyclic monophosphate-specific phosphodiesterase activity. J Neurosci 4:495–501
    [Google Scholar]
  62. Yu S. L., Lee S. K., Alexander H., Alexander S. 1998; Rapid changes of nucleotide excision repair gene expression following Uv-irradiation and cisplatin treatment of Dictyostelium discoideum. Nucleic Acids Res 26:3397–3403 [CrossRef]
    [Google Scholar]
  63. Yuan Z. M., Shioya H., Ishiko T.7 other authors 1999; p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399:814–817 erratum 400 792 [CrossRef]
    [Google Scholar]
/content/journal/micro/10.1099/00221287-146-9-2219
Loading
/content/journal/micro/10.1099/00221287-146-9-2219
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error