Drug Resistance and the Tumor Suppressor p53: The Paradox of Wild-Type Genotype in Chemorefractory Cancers

  • Zahid H. SiddikEmail author


The tumor suppressor p53 has a central role in drug-induced cell death. Its mutation in about 50% of all cancers is a source of drug resistance from the loss in apoptotic signaling, but loss of apoptosis is also found in many resistant tumors that retain wild-type p53 and this represents a paradox. Indeed, resistance seems to be substantially greater with wild-type p53 present as compared to mutant p53. From the perspective of response and survival in cancer patients, responses are observed independent of p53 gene status, but the 5-year survival rate is significantly greater when wild-type p53 is present. This indicates that an effort to increase the response rate in cancers having the wild-type p53 should translate into an increase in the survival rate. To accomplish this goal, an understanding of the mechanisms contributing to resistance in wild-type p53 cancers becomes important. These mechanisms are multifactorial and include loss in DNA damage recognition, alterations in post-translational modification of p53, failure to activate p53 due to target gene silencing, and failure to transrepress antiapoptotic genes.


p53 gene status DNA damage recognition Post-translational modification Transactivation Transrepression Apoptosis 



Supported by NIH Grant RO1 CA127263.


  1. Allan, L. A., Duhig, T., Read, M., and Fried, M. 2000. The p21(WAF1/CIP1) promoter is methylated in Rat-1 cells: stable restoration of p53-dependent p21(WAF1/CIP1) expression after transfection of a genomic clone containing the p21(WAF1/CIP1) gene. Mol. Cell Biol. 20:1291–1298.PubMedCrossRefGoogle Scholar
  2. Antoni, L., Sodha, N., Collins, I., and Garrett, M. D. 2007. CHK2 kinase: cancer susceptibility and cancer therapy – two sides of the same coin? Nat. Rev. Cancer 7:925–936.PubMedCrossRefGoogle Scholar
  3. Aquilina, G., Ceccotti, S., Martinelli, S., Soddu, S., Crescenzi, M., Branch, P., Karran, P., and Bignami, M. 2000. Mismatch repair and p53 independently affect sensitivity to N-(2- chloroethyl)-N'-cyclohexyl-N-nitrosourea. Clin. Cancer Res. 6:671–680.PubMedGoogle Scholar
  4. Attardi, L. D., Lowe, S. W., Brugarolas, J., and Jacks, T. 1996. Transcriptional activation by p53, but not induction of the p21 gene, is essential for oncogene-mediated apoptosis. EMBO J. 15:3693–3701.PubMedGoogle Scholar
  5. Baldassarre, G., Belletti, B., Battista, S., Nicoloso, M. S., Pentimalli, F., Fedele, M., Croce, C. M., and Fusco, A. 2005. HMGA1 protein expression sensitizes cells to cisplatin-induced cell death. Oncogene 24:6809–6819.PubMedCrossRefGoogle Scholar
  6. Banin, S., Moyal, L., Shieh, S., Taya, Y., Anderson, C. W., Chessa, L., Smorodinsky, N. I., Prives, C., Reiss, Y., Shiloh, Y., and Ziv, Y. 1998. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281:1674–1677.PubMedCrossRefGoogle Scholar
  7. Barboza, J. A., Liu, G., Ju, Z., El Naggar, A. K., and Lozano, G. 2006. p21 delays tumor onset by preservation of chromosomal stability. Proc. Natl. Acad. Sci. U. S. A 103:19842–19847.Google Scholar
  8. Bargonetti, J., and Manfredi, J. J. 2002. Multiple roles of the tumor suppressor p53. Curr. Opin. Oncol. 14:86–91.PubMedCrossRefGoogle Scholar
  9. Bartussek, C., Naumann, U., and Weller, M. 1999. Accumulation of mutant p53(V143A) modulates the growth, clonogenicity, and radiochemosensitivity of malignant glioma cells independent of endogenous p53 status. Exp. Cell Res. 253:432–439.PubMedCrossRefGoogle Scholar
  10. Berns, E. M., Foekens, J. A., Vossen, R., Look, M. P., Devilee, P., Henzen-Logmans, S. C., van Staveren, I. L., van Putten, W. L., Inganas, M., Meijer-van Gelder, M. E., Cornelisse, C., Claassen, C. J., Portengen, H., Bakker, B., and Klijn, J. G. 2000. Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer. Cancer Res. 60:2155–2162.PubMedGoogle Scholar
  11. Blagosklonny, M. V., Giannakakou, P., Romanova, L. Y., Ryan, K. M., Vousden, K. H., and Fojo, T. 2001. Inhibition of HIF-1- and wild-type p53-stimulated transcription by codon Arg175 p53 mutants with selective loss of functions. Carcinogenesis 22:861–867.PubMedCrossRefGoogle Scholar
  12. Blandino, G., Levine, A. J., and Oren, M. 1999. Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene 18:477–485.PubMedCrossRefGoogle Scholar
  13. Bradford, C. R., Zhu, S., Ogawa, H., Ogawa, T., Ubell, M., Narayan, A., Johnson, G., Wolf, G. T., Fisher, S. G., and Carey, T. E. 2003. P53 mutation correlates with cisplatin sensitivity in head and neck squamous cell carcinoma lines. Head Neck 25:654–661.PubMedCrossRefGoogle Scholar
  14. Brezniceanu, M. L., Volp, K., Bosser, S., Solbach, C., Lichter, P., Joos, S., and Zornig, M. 2003. HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma. FASEB J. 17:1295–1297.PubMedGoogle Scholar
  15. Brown, E. J., and Baltimore, D. 2000. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14:397–402.PubMedGoogle Scholar
  16. Burdak-Rothkamm, S., Rothkamm, K., and Prise, K. M. 2008. ATM acts downstream of ATR in the DNA damage response signaling of bystander cells. Cancer Res. 68:7059–7065.PubMedCrossRefGoogle Scholar
  17. Burger, H., Nooter, K., Boersma, A. W., Kortland, C. J., and Stoter, G. 1998. Expression of p53, Bcl-2 and Bax in cisplatin-induced apoptosis in testicular germ cell tumour cell lines. Br. J. Cancer 77:1562–1567.PubMedCrossRefGoogle Scholar
  18. Canman, C. E., Lim, D. S., Cimprich, K. A., Taya, Y., Tamai, K., Sakaguchi, K., Appella, E., Kastan, M. B., and Siliciano, J. D. 1998. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281:1677–1679.PubMedCrossRefGoogle Scholar
  19. Chaney, S. G., Campbell, S. L., Bassett, E., and Wu, Y. 2005. Recognition and processing of cisplatin- and oxaliplatin-DNA adducts. Crit Rev. Oncol. Hematol. 53:3–11.PubMedCrossRefGoogle Scholar
  20. Chaney, S. G., and Vaisman, A. 1999. Specificity of platinum-DNA adduct repair. J. Inorg. Biochem. 77:71–81.PubMedCrossRefGoogle Scholar
  21. Chene, P. 2003. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nat. Rev. Cancer 3:102–109.PubMedCrossRefGoogle Scholar
  22. Cliby, W. A., Roberts, C. J., Cimprich, K. A., Stringer, C. M., Lamb, J. R., Schreiber, S. L., and Friend, S. H. 1998. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 17:159–169.PubMedCrossRefGoogle Scholar
  23. Damia, G., Filiberti, L., Vikhanskaya, F., Carrassa, L., Taya, Y., D'Incalci, M., and Broggini, M. 2001. Cisplatinum and taxol induce different patterns of p53 phosphorylation. Neoplasia 3:10–16.PubMedCrossRefGoogle Scholar
  24. Delavaine, L., and La Thangue, N. B. 1999. Control of E2F activity by p21Waf1/Cip1. Oncogene 18:5381–5392.PubMedCrossRefGoogle Scholar
  25. Delmastro, D. A., Li, J., Vaisman, A., Solle, M., and Chaney, S. G. 1997. DNA damage inducible-gene expression following platinum treatment in human ovarian carcinoma cell lines. Cancer Chemother. Pharmacol. 39:245–253.PubMedGoogle Scholar
  26. Dressman, H. K., Berchuck, A., Chan, G., Zhai, J., Bild, A., Sayer, R., Cragun, J., Clarke, J., Whitaker, R. S., Li, L., Gray, J., Marks, J., Ginsburg, G. S., Potti, A., West, M., Nevins, J. R., and Lancaster, J. M. 2007. An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. J. Clin. Oncol. 25:517–525.PubMedCrossRefGoogle Scholar
  27. el Deiry, W. S. 2003. The role of p53 in chemosensitivity and radiosensitivity. Oncogene 22:7486–7495.PubMedCrossRefGoogle Scholar
  28. Fan, S., Chang, J. K., Smith, M. L., Duba, D., Fornace, A. J., Jr., and O'Connor, P. M. 1997. Cells lacking CIP1/WAF1 genes exhibit preferential sensitivity to cisplatin and nitrogen mustard. Oncogene 14:2127–2136.PubMedCrossRefGoogle Scholar
  29. Fan, S., Smith, M. L., Rivet, D. J., Duba, D., Zhan, Q., Kohn, K. W., Fornace, A. J., Jr., and O'Connor, P. M. 1995. Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. Cancer Res. 55:1649–1654.PubMedGoogle Scholar
  30. Fink, D., Aebi, S., and Howell, S. B. 1998. The role of DNA mismatch repair in drug resistance. Clin. Cancer Res. 4:1–6.PubMedGoogle Scholar
  31. Fojta, M., Pivonkova, H., Brazdova, M., Kovarova, L., Palecek, E., Pospisilova, S., Vojtesek, B., Kasparkova, J., and Brabec, V. 2003. Recognition of DNA modified by antitumor cisplatin by "latent" and "active" protein p53. Biochem. Pharmacol. 65:1305–1316.PubMedCrossRefGoogle Scholar
  32. Friess, H., Lu, Z., Graber, H. U., Zimmermann, A., Adler, G., Korc, M., Schmid, R. M., and Buchler, M. W. 1998. Bax, but not bcl-2, influences the prognosis of human pancreatic cancer. Gut 43:414–421.PubMedCrossRefGoogle Scholar
  33. Gartel, A. L., and Radhakrishnan, S. K. 2005. Lost in transcription: p21 repression, mechanisms, and consequences. Cancer Res. 65:3980–3985.PubMedCrossRefGoogle Scholar
  34. Gartel, A. L., and Tyner, A. L. 2002. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol. Cancer Ther. 1:639–649.PubMedGoogle Scholar
  35. Geisler, S., Lonning, P. E., Aas, T., Johnsen, H., Fluge, O., Haugen, D. F., Lillehaug, J. R., Akslen, L. A., and Borresen-Dale, A. L. 2001. Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer. Cancer Res. 61:2505–2512.PubMedGoogle Scholar
  36. Giaccone, G. 2000. Clinical perspectives on platinum resistance. Drugs 59 Suppl 4:9–17.PubMedCrossRefGoogle Scholar
  37. Gottifredi, V., Karni-Schmidt, O., Shieh, S. S., and Prives, C. 2001. p53 down-regulates CHK1 through p21 and the retinoblastoma protein. Mol. Cell Biol. 21:1066–1076.PubMedCrossRefGoogle Scholar
  38. Hagopian, G. S., Mills, G. B., Khokhar, A. R., Bast, R. C., Jr., and Siddik, Z. H. 1999. Expression of p53 in cisplatin-resistant ovarian cancer cell lines: modulation with the novel platinum analogue (1R, 2R- diaminocyclohexane)(trans-diacetato)(dichloro)-platinum(IV). Clin. Cancer Res. 5:655–663.PubMedGoogle Scholar
  39. Harris, S. L., and Levine, A. J. 2005. The p53 pathway: positive and negative feedback loops. Oncogene 24:2899–2908.PubMedCrossRefGoogle Scholar
  40. Hastak, K., Agarwal, M. K., Mukhtar, H., and Agarwal, M. L. 2005. Ablation of either p21 or Bax prevents p53-dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate. FASEB J. 19:789–791.PubMedGoogle Scholar
  41. Hawkins, D. S., Demers, G. W., and Galloway, D. A. 1996. Inactivation of p53 enhances sensitivity to multiple chemotherapeutic agents. Cancer Res. 56:892–898.PubMedGoogle Scholar
  42. He, Q., Liang, C. H., and Lippard, S. J. 2000. Steroid hormones induce HMG1 overexpression and sensitize breast cancer cells to cisplatin and carboplatin. Proc. Natl. Acad. Sci. U. S. A 97:5768–5772.Google Scholar
  43. Helleman, J., Jansen, M. P., Span, P. N., van Staveren, I. L., Massuger, L. F., Meijer-van Gelder, M. E., Sweep, F. C., Ewing, P. C., van der Burg, M. E., Stoter, G., Nooter, K., and Berns, E. M. 2006. Molecular profiling of platinum resistant ovarian cancer. Int. J. Cancer 118:1963–1971.PubMedCrossRefGoogle Scholar
  44. Helton, E. S., and Chen, X. 2007. p53 modulation of the DNA damage response. J. Cell Biochem. 100:883–896.PubMedCrossRefGoogle Scholar
  45. Herzog, K. H., Chong, M. J., Kapsetaki, M., Morgan, J. I., and McKinnon, P. J. 1998. Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 280:1089–1091.PubMedCrossRefGoogle Scholar
  46. Hollstein, M., Sidransky, D., Vogelstein, B., and Harris, C. C. 1991. p53 mutations in human cancers. Science 253:49–53.PubMedCrossRefGoogle Scholar
  47. Horn, H. F., and Vousden, K. H. 2007. Coping with stress: multiple ways to activate p53. Oncogene 26:1306–1316.PubMedCrossRefGoogle Scholar
  48. Iliakis, G., Wang, Y., Guan, J., and Wang, H. 2003. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene 22:5834–5847.PubMedCrossRefGoogle Scholar
  49. Imamura, T., Izumi, H., Nagatani, G., Ise, T., Nomoto, M., Iwamoto, Y., and Kohno, K. 2001. Interaction with p53 enhances binding of cisplatin-modified DNA by high mobility group 1 protein. J. Biol. Chem. 276:7534–7540.PubMedCrossRefGoogle Scholar
  50. Ismail, R. S., Baldwin, R. L., Fang, J., Browning, D., Karlan, B. Y., Gasson, J. C., and Chang, D. D. 2000. Differential gene expression between normal and tumor-derived ovarian epithelial cells. Cancer Res. 60:6744–6749.PubMedGoogle Scholar
  51. Jack, M. T., Woo, R. A., Hirao, A., Cheung, A., Mak, T. W., and Lee, P. W. 2002. Chk2 is dispensable for p53-mediated G1 arrest but is required for a latent p53-mediated apoptotic response. Proc. Natl. Acad. Sci. U. S. A 99:9825–9829.Google Scholar
  52. Jayaraman, L., Moorthy, N. C., Murthy, K. G., Manley, J. L., Bustin, M., and Prives, C. 1998. High mobility group protein-1 (HMG-1) is a unique activator of p53. Genes Dev. 12:462–472.PubMedCrossRefGoogle Scholar
  53. Jekunen, A. P., Christen, R. D., Shalinsky, D. R., and Howell, S. B. 1994. Synergistic interaction between cisplatin and taxol in human ovarian carcinoma cells in vitro. Br. J. Cancer 69:299–306.PubMedCrossRefGoogle Scholar
  54. Johnson, S. W., Laub, P. B., Beesley, J. S., Ozols, R. F., and Hamilton, T. C. 1997. Increased platinum-DNA damage tolerance is associated with cisplatin resistance and cross-resistance to various chemotherapeutic agents in unrelated human ovarian cancer cell lines. Cancer Res 57:850–856.PubMedGoogle Scholar
  55. Kandioler-Eckersberger, D., Ludwig, C., Rudas, M., Kappel, S., Janschek, E., Wenzel, C., Schlagbauer-Wadl, H., Mittlbock, M., Gnant, M., Steger, G., and Jakesz, R. 2000. TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin. Cancer Res. 6:50–56.PubMedGoogle Scholar
  56. Kapoor, M., Hamm, R., Yan, W., Taya, Y., and Lozano, G. 2000. Cooperative phosphorylation at multiple sites is required to activate p53 in response to UV radiation. Oncogene 19:358–364.PubMedCrossRefGoogle Scholar
  57. Kastan, M. B. 2007. Wild-type p53: tumors can't stand it. Cell 128:837–840.PubMedCrossRefGoogle Scholar
  58. Kester, H. A., Sonneveld, E., van der Saag, P. T., and van der, B. B. 2003. Prolonged progestin treatment induces the promoter of CDK inhibitor p21 Cip1,Waf1 through activation of p53 in human breast and endometrial tumor cells. Exp. Cell Res. 284:264–273.PubMedCrossRefGoogle Scholar
  59. Kim, B. J., Ryu, S. W., and Song, B. J. 2006. JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J. Biol. Chem. 281:21256–21265.PubMedCrossRefGoogle Scholar
  60. King, T. C., Akerley, W., Fan, A. C., Moore, T., Mangray, S., Hsiu, C. M., and Safran, H. 2000. p53 mutations do not predict response to paclitaxel in metastatic nonsmall cell lung carcinoma. Cancer 89:769–773.PubMedCrossRefGoogle Scholar
  61. Knudson, C. M., Johnson, G. M., Lin, Y., and Korsmeyer, S. J. 2001. Bax accelerates tumorigenesis in p53-deficient mice. Cancer Res. 61:659–665.PubMedGoogle Scholar
  62. Kojima, K., Konopleva, M., McQueen, T., O'Brien, S., Plunkett, W., and Andreeff, M. 2006. Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood 108:993–1000.PubMedCrossRefGoogle Scholar
  63. Krajewski, S., Blomqvist, C., Franssila, K., Krajewska, M., Wasenius, V. M., Niskanen, E., Nordling, S., and Reed, J. C. 1995. Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. Cancer Res. 55:4471–4478.PubMedGoogle Scholar
  64. Lage, H., and Dietel, M. 1999. Involvement of the DNA mismatch repair system in antineoplastic drug resistance. J. Cancer Res. Clin. Oncol. 125:156–165.PubMedCrossRefGoogle Scholar
  65. Lagger, G., Doetzlhofer, A., Schuettengruber, B., Haidweger, E., Simboeck, E., Tischler, J., Chiocca, S., Suske, G., Rotheneder, H., Wintersberger, E., and Seiser, C. 2003. The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene. Mol. Cell Biol. 23:2669–2679.PubMedCrossRefGoogle Scholar
  66. Lavarino, C., Pilotti, S., Oggionni, M., Gatti, L., Perego, P., Bresciani, G., Pierotti, M. A., Scambia, G., Ferrandina, G., Fagotti, A., Mangioni, C., Lucchini, V., Vecchione, F., Bolis, G., Scarfone, G., and Zunino, F. 2000. p53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma. J. Clin. Oncol. 18:3936–3945.PubMedGoogle Scholar
  67. Lavin, M. F., and Gueven, N. 2006. The complexity of p53 stabilization and activation. Cell Death. Differ. 13:941–950.PubMedCrossRefGoogle Scholar
  68. Lee, M. H., and Lozano, G. 2006. Regulation of the p53-MDM2 pathway by 14-3-3 sigma and other proteins. Semin. Cancer Biol. 16:225–234.PubMedCrossRefGoogle Scholar
  69. Levesque, A. A., and Eastman, A. 2007. p53-based cancer therapies: Is defective p53 the Achilles heel of the tumor? Carcinogenesis 28:13–20.PubMedCrossRefGoogle Scholar
  70. Lin, X., Ramamurthi, K., Mishima, M., Kondo, A., Christen, R. D., and Howell, S. B. 2001. P53 modulates the effect of loss of DNA mismatch repair on the sensitivity of human colon cancer cells to the cytotoxic and mutagenic effects of cisplatin. Cancer Res. 61:1508–1516.PubMedGoogle Scholar
  71. Lincet, H., Poulain, L., Remy, J. S., Deslandes, E., Duigou, F., Gauduchon, P., and Staedel, C. 2000. The p21(cip1/waf1) cyclin-dependent kinase inhibitor enhances the cytotoxic effect of cisplatin in human ovarian carcinoma cells. Cancer Lett. 161:17–26.PubMedCrossRefGoogle Scholar
  72. Liu, G., and Lozano, G. 2005. p21 stability: linking chaperones to a cell cycle checkpoint. Cancer Cell 7:113–114.PubMedCrossRefGoogle Scholar
  73. Liu, S., Bishop, W. R., and Liu, M. 2003. Differential effects of cell cycle regulatory protein p21(WAF1/Cip1) on apoptosis and sensitivity to cancer chemotherapy. Drug Resist. Updat. 6:183–195.PubMedCrossRefGoogle Scholar
  74. Lohr, K., Moritz, C., Contente, A., and Dobbelstein, M. 2003. p21/CDKN1A mediates negative regulation of transcription by p53. J. Biol. Chem. 278:32507–32516.PubMedCrossRefGoogle Scholar
  75. Luo, Y., Lin, F. T., and Lin, W. C. 2004. ATM-mediated stabilization of hMutL DNA mismatch repair proteins augments p53 activation during DNA damage. Mol. Cell Biol. 24:6430–6444.PubMedCrossRefGoogle Scholar
  76. Martin-Caballero, J., Flores, J. M., Garcia-Palencia, P., and Serrano, M. 2001. Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. Cancer Res. 61:6234–6238.PubMedGoogle Scholar
  77. Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R., III, Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y., Shiloh, Y., Gygi, S. P., and Elledge, S. J. 2007. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316:1160–1166.PubMedCrossRefGoogle Scholar
  78. Mayer, F., Honecker, F., Looijenga, L. H., and Bokemeyer, C. 2003. Towards an understanding of the biological basis of response to cisplatin-based chemotherapy in germ-cell tumors. Ann. Oncol. 14:825–832.PubMedCrossRefGoogle Scholar
  79. McCurrach, M. E., Connor, T. M., Knudson, C. M., Korsmeyer, S. J., and Lowe, S. W. 1997. Bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proc. Natl. Acad. Sci. U. S. A 94:2345–2349.Google Scholar
  80. Miquel, C., Borrini, F., Grandjouan, S., Auperin, A., Viguier, J., Velasco, V., Duvillard, P., Praz, F., and Sabourin, J. C. 2005. Role of bax mutations in apoptosis in colorectal cancers with microsatellite instability. Am. J. Clin. Pathol. 123:562–570.PubMedCrossRefGoogle Scholar
  81. Mujoo, K., Watanabe, M., Nakamura, J., Khokhar, A. R., and Siddik, Z. H. 2003. Status of p53 phosphorylation and function in sensitive and resistant human cancer models exposed to platinum-based DNA damaging agents. J. Cancer Res. Clin. Oncol. 129:709–718.PubMedCrossRefGoogle Scholar
  82. Nagatani, G., Nomoto, M., Takano, H., Ise, T., Kato, K., Imamura, T., Izumi, H., Makishima, K., and Kohno, K. 2001. Transcriptional activation of the human HMG1 gene in cisplatin- resistant human cancer cells. Cancer Res. 61:1592–1597.PubMedGoogle Scholar
  83. O’Connor, P. M., Jackman, J., Bae, I., Myers, T. G., Fan, S., Mutoh, M., Scudiero, D. A., Monks, A., Sausville, E. A., Weinstein, J. N., Friend, S., Fornace, A. J. Jr., and Kohn, K. W. 1997. Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res. 57:4285–4300.PubMedGoogle Scholar
  84. Ozols, R. F. 1991. Ovarian cancer: new clinical approaches. Cancer Treat. Rev 18 Suppl A:77–83.PubMedCrossRefGoogle Scholar
  85. Perego, P., Gatti, L., Righetti, S. C., Beretta, G. L., Carenini, N., Corna, E., Dal Bo, L., Tinelli, S., Colangelo, D., Leone, R., Apostoli, P., Lombardi, L., Beggiolin, G., Piazzoni, L., and Zunino, F. 2003. Development of resistance to a trinuclear platinum complex in ovarian carcinoma cells. Int. J. Cancer 105:617–624.PubMedCrossRefGoogle Scholar
  86. Pietenpol, J. A., and Stewart, Z. A. 2002. Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology 181–182:475–481.PubMedCrossRefGoogle Scholar
  87. Poole, A. J., Heap, D., Carroll, R. E., and Tyner, A. L. 2004. Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon. Oncogene 23:8128–8134.PubMedCrossRefGoogle Scholar
  88. Puca, R., Nardinocchi, L., Gal, H., Rechavi, G., Amariglio, N., Domany, E., Notterman, D. A., Scarsella, M., Leonetti, C., Sacchi, A., Blandino, G., Givol, D., and D'Orazi, G. 2008. Reversible dysfunction of wild-type p53 following homeodomain-interacting protein kinase-2 knockdown. Cancer Res. 68:3707–3714.PubMedCrossRefGoogle Scholar
  89. Qin, L. F., and Ng, I. O. 2001. Exogenous expression of p21(WAF1/CIP1) exerts cell growth inhibition and enhances sensitivity to cisplatin in hepatoma cells. Cancer Lett. 172:7–15.PubMedCrossRefGoogle Scholar
  90. Reles, A., Wen, W. H., Schmider, A., Gee, C., Runnebaum, I. B., Kilian, U., Jones, L. A., El Naggar, A., Minguillon, C., Schonborn, I., Reich, O., Kreienberg, R., Lichtenegger, W., and Press, M. F. 2001. Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer. Clin. Cancer Res. 7:2984–2997.PubMedGoogle Scholar
  91. Righetti, S. C., Della, T. G., Pilotti, S., Menard, S., Ottone, F., Colnaghi, M. I., Pierotti, M. A., Lavarino, C., Cornarotti, M., Oriana, S., Bohm, S., Bresciani, G. L., Spatti, G., and Zunino, F. 1996. A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma. Cancer Res. 56:689–693.PubMedGoogle Scholar
  92. Roberts, D., Schick, J., Conway, S., Biade, S., Laub, P. B., Stevenson, J. P., Hamilton, T. C., O'Dwyer, P. J., and Johnson, S. W. 2005. Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells. Br. J. Cancer 92:1149–1158.PubMedCrossRefGoogle Scholar
  93. Roemer, K. 1999. Mutant p53: gain-of-function oncoproteins and wild-type p53 inactivators. Biol. Chem. 380:879–887.PubMedCrossRefGoogle Scholar
  94. Roman-Gomez, J., Castillejo, J. A., Jimenez, A., Gonzalez, M. G., Moreno, F., Rodriguez, M. C., Barrios, M., Maldonado, J., and Torres, A. 2002. 5' CpG island hypermethylation is associated with transcriptional silencing of the p21(CIP1/WAF1/SDI1) gene and confers poor prognosis in acute lymphoblastic leukemia. Blood 99:2291–2296.PubMedCrossRefGoogle Scholar
  95. Rose, S. L., Goodheart, M. J., DeYoung, B. R., Smith, B. J., and Buller, R. E. 2003. p21 expression predicts outcome in p53-null ovarian carcinoma. Clin. Cancer Res. 9:1028–1032.PubMedGoogle Scholar
  96. Samuel, T., Weber, H. O., and Funk, J. O. 2002. Linking DNA damage to cell cycle checkpoints. Cell Cycle 1:162–168.PubMedCrossRefGoogle Scholar
  97. Sarkis, A. S., Bajorin, D. F., Reuter, V. E., Herr, H. W., Netto, G., Zhang, Z. F., Schultz, P. K., Cordon-Cardo, C., and Scher, H. I. 1995. Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J. Clin. Oncol. 13: 1384–1390.PubMedGoogle Scholar
  98. Schmidt, M., Bachhuber, A., Victor, A., Steiner, E., Mahlke, M., Lehr, H. A., Pilch, H., Weikel, W., and Knapstein, P. G. 2003. p53 expression and resistance against paclitaxel in patients with metastatic breast cancer. J. Cancer Res. Clin. Oncol. 129:295–302.PubMedGoogle Scholar
  99. Schuler, M., and Green, D. R. 2005. Transcription, apoptosis and p53: catch-22. Trends Genet. 21:182–187.PubMedCrossRefGoogle Scholar
  100. Scott, S. L., Earle, J. D., and Gumerlock, P. H. 2003. Functional p53 increases prostate cancer cell survival after exposure to fractionated doses of ionizing radiation. Cancer Res. 63:7190–7196.PubMedGoogle Scholar
  101. Shats, I., Milyavsky, M., Tang, X., Stambolsky, P., Erez, N., Brosh, R., Kogan, I., Braunstein, I., Tzukerman, M., Ginsberg, D., and Rotter, V. 2004. p53-dependent down-regulation of telomerase is mediated by p21waf1. J. Biol. Chem. 279:50976–50985.PubMedCrossRefGoogle Scholar
  102. Shen, L., Kondo, Y., Hamilton, S. R., Rashid, A., and Issa, J. P. 2003. P14 methylation in human colon cancer is associated with microsatellite instability and wild-type p53. Gastroenterology 124:626–633.PubMedCrossRefGoogle Scholar
  103. Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y., and Prives, C. 2000. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 14:289–300.PubMedGoogle Scholar
  104. Shoji, T., Tanaka, F., Takata, T., Yanagihara, K., Otake, Y., Hanaoka, N., Miyahara, R., Nakagawa, T., Kawano, Y., Ishikawa, S., Katakura, H., and Wada, H. 2002. Clinical significance of p21 expression in non-small-cell lung cancer. J. Clin. Oncol. 20:3865–3871.PubMedCrossRefGoogle Scholar
  105. Siddik, Z. H., Mims, B., Lozano, G., and Thai, G. 1998. Independent pathways of p53 induction by cisplatin and X-rays in a cisplatin-resistant ovarian tumor cell line. Cancer Res. 58:698–703.PubMedGoogle Scholar
  106. Soussi, T. 2000. The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann. N. Y. Acad. Sci. 910:121–137.PubMedCrossRefGoogle Scholar
  107. Stewart, J. J., White, J. T., Yan, X., Collins, S., Drescher, C. W., Urban, N. D., Hood, L., and Lin, B. 2006. Proteins associated with Cisplatin resistance in ovarian cancer cells identified by quantitative proteomic technology and integrated with mRNA expression levels. Mol. Cell Proteomics. 5:433–443.PubMedGoogle Scholar
  108. Stojic, L., Brun, R., and Jiricny, J. 2004. Mismatch repair and DNA damage signalling. DNA Repair (Amst) 3:1091–1101.CrossRefGoogle Scholar
  109. Sturm, I., Kohne, C. H., Wolff, G., Petrowsky, H., Hillebrand, T., Hauptmann, S., Lorenz, M., Dorken, B., and Daniel, P. T. 1999. Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative prognostic factor in patients with resected liver metastases. J. Clin. Oncol. 17:1364–1374.PubMedGoogle Scholar
  110. Sturm, I., Papadopoulos, S., Hillebrand, T., Benter, T., Luck, H. J., Wolff, G., Dorken, B., and Daniel, P. T. 2000. Impaired BAX protein expression in breast cancer: mutational analysis of the BAX and the p53 gene. Int. J. Cancer 87:517–521.PubMedCrossRefGoogle Scholar
  111. Tang, X., Milyavsky, M., Shats, I., Erez, N., Goldfinger, N., and Rotter, V. 2004. Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene 23:5759–5769.PubMedCrossRefGoogle Scholar
  112. Theard, D., Coisy, M., Ducommun, B., Concannon, P., and Darbon, J. M. 2001. Etoposide and adriamycin but not genistein can activate the checkpoint kinase Chk2 independently of ATM/ATR. Biochem. Biophys. Res. Commun. 289:1199–1204.PubMedCrossRefGoogle Scholar
  113. Thornborrow, E. C., and Manfredi, J. J. 2001. The tumor suppressor protein p53 requires a cofactor to activate transcriptionally the human BAX promoter. J. Biol. Chem. 276:15598–15608.PubMedCrossRefGoogle Scholar
  114. Toledo, F., and Wahl, G. M. 2006. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat. Rev. Cancer 6:909–923.PubMedCrossRefGoogle Scholar
  115. Troester, M. A., Hoadley, K. A., Sorlie, T., Herbert, B. S., Borresen-Dale, A. L., Lonning, P. E., Shay, J. W., Kaufmann, W. K., and Perou, C. M. 2004. Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 64:4218–4226.PubMedCrossRefGoogle Scholar
  116. Vaisman, A., Varchenko, M., Umar, A., Kunkel, T. A., Risinger, J. I., Barrett, J. C., Hamilton, T. C., and Chaney, S. G. 1998. The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum- DNA adducts. Cancer Res. 58:3579–3585.PubMedGoogle Scholar
  117. van der Zee, A. G., Hollema, H., Suurmeijer, A. J., Krans, M., Sluiter, W. J., Willemse, P. H., Aalders, J. G., and de Vries, E. G. 1995. Value of P-glycoprotein, glutathione S-transferase pi, c-erbB-2, and p53 as prognostic factors in ovarian carcinomas. J. Clin. Oncol. 13:70–78.PubMedGoogle Scholar
  118. Vekris, A., Meynard, D., Haaz, M. C., Bayssas, M., Bonnet, J., and Robert, J. 2004. Molecular determinants of the cytotoxicity of platinum compounds: the contribution of in silico research. Cancer Res. 64:356–362.PubMedCrossRefGoogle Scholar
  119. Villunger, A., Michalak, E. M., Coultas, L., Mullauer, F., Bock, G., Ausserlechner, M. J., Adams, J. M., and Strasser, A. 2003. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302:1036–1038.PubMedCrossRefGoogle Scholar
  120. Vousden, K. H., and Lu, X. 2002. Live or let die: the cell's response to p53. Nat. Rev. Cancer 2:594–604.PubMedCrossRefGoogle Scholar
  121. Willis, A., Jung, E. J., Wakefield, T., and Chen, X. 2004. Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. Oncogene 23:2330–2338.PubMedCrossRefGoogle Scholar
  122. Wright, J. A., Keegan, K. S., Herendeen, D. R., Bentley, N. J., Carr, A. M., Hoekstra, M. F., and Concannon, P. 1998. Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control. Proc. Natl. Acad. Sci. U. S. A 95:7445–7450.Google Scholar
  123. Wu, Q., Kirschmeier, P., Hockenberry, T., Yang, T. Y., Brassard, D. L., Wang, L., McClanahan, T., Black, S., Rizzi, G., Musco, M. L., Mirza, A., and Liu, S. 2002. Transcriptional regulation during p21WAF1/CIP1-induced apoptosis in human ovarian cancer cells. J. Biol. Chem. 277:36329–36337.PubMedCrossRefGoogle Scholar
  124. Zaffaroni, N., Silvestrini, R., Orlandi, L., Bearzatto, A., Gornati, D., and Villa, R. 1998. Induction of apoptosis by taxol and cisplatin and effect on cell cycle- related proteins in cisplatin-sensitive and -resistant human ovarian cells. Br. J. Cancer 77:1378–1385.PubMedCrossRefGoogle Scholar
  125. Zhang, L., Zhou, W., Velculescu, V. E., Kern, S. E., Hruban, R. H., Hamilton, S. R., Vogelstein, B., and Kinzler, K. W. 1997. Gene expression profiles in normal and cancer cells. Science 276:1268–1272.PubMedCrossRefGoogle Scholar
  126. Zhang, N., Song, Q., Lu, H., and Lavin, M. F. 1996. Induction of p53 and increased sensitivity to cisplatin in ataxia-telangiectasia cells. Oncogene 13:655–659.PubMedGoogle Scholar
  127. Zhang, P., Gao, W., Li, H., Reed, E., and Chen, F. 2005a. Inducible degradation of checkpoint kinase 2 links to cisplatin-induced resistance in ovarian cancer cells. Biochem. Biophys. Res. Commun. 328:567–572.CrossRefGoogle Scholar
  128. Zhang, P., Wang, J., Gao, W., Yuan, B. Z., Rogers, J., and Reed, E. 2004. CHK2 kinase expression is down-regulated due to promoter methylation in non-small cell lung cancer. Mol. Cancer 3:14.PubMedCrossRefGoogle Scholar
  129. Zhang, Y., Ma, W. Y., Kaji, A., Bode, A. M., and Dong, Z. 2002. Requirement of ATM in UVA-induced signaling and apoptosis. J. Biol. Chem. 277:3124–3131.PubMedCrossRefGoogle Scholar
  130. Zhang, Y. W., Otterness, D. M., Chiang, G. G., Xie, W., Liu, Y. C., Mercurio, F., and Abraham, R. T. 2005b. Genotoxic stress targets human Chk1 for degradation by the ubiquitin-proteasome pathway. Mol. Cell 19:607–618.PubMedCrossRefGoogle Scholar
  131. Zhou, B. B., and Sausville, E. A. 2003. Drug discovery targeting Chk1 and Chk2 kinases. Prog. Cell Cycle Res. 5:413–421.PubMedGoogle Scholar
  132. Zhu, W. G., Srinivasan, K., Dai, Z., Duan, W., Druhan, L. J., Ding, H., Yee, L., Villalona-Calero, M. A., Plass, C., and Otterson, G. A. 2003. Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter. Mol. Cell Biol. 23:4056–4065.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Experimental TherapeuticsBox 353, The University of Texas M. D. Anderson Cancer CenterHoustonUSA

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