Home LiteratureArticle Details
PMID: 18060030 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice.

The Journal of clinical investigation ·Vol. 117 ·No. 12 ·2007-12-00 ·Pages 3753-64

Tang X, Zhu Y, Han L, Kim AL, Kopelovich L, Bickers DR, Athar M

Abstract

Mutations in the tumor suppressor p53 are detectable in over 50% of all human malignancies. Mutant p53 protein is incapable of transactivating its downstream target genes that are required for DNA repair and apoptosis. Chronic exposure to UVB induces p53 mutations and is carcinogenic in both murine and human skin. CP-31398, a styrylquinazoline compound, restores the tumor suppressor functions of mutant forms of p53 in tumor cells. However, its effectiveness in vivo remains unclear. Here, we demonstrate that CP-31398 blocked UVB-induced skin carcinogenesis and was associated with increases in p53, p21, and BclXs. CP-31398 downregulated Bcl2, proliferating nuclear cell antigen, and cyclin D1. Activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase also occurred in both tumor and perilesional skin following treatment. CP-31398 induced the expression of p53-dependent target proteins, and this was followed by apoptosis in UVB-irradiated wild-type mice but not in their p53-deficient littermates. Similar effects were observed in human skin carcinoma A431 cells expressing mutant p53. In addition, CP-31398 induced mitochondrial translocation of p53, leading to changes in mitochondrial membrane permeability pore transition (MPT) and consequent cytochrome c release in these cells. Blocking MPT diminished p53 translocation and apoptosis. These studies indicate that reconstituting p53 tumor suppressor functions in vivo by small molecular weight compounds may block the pathogenesis and progression of skin cancer.

MeSH Terms
Animals Apoptosis/drug effects,genetics,radiation effects Caspase 3/genetics,metabolism Cell Line, Tumor Cell Transformation, Neoplastic/drug effects,genetics,metabolism,pathology,radiation effects Cyclin D Cyclins/genetics,metabolism Cytochromes c/genetics,metabolism Environmental Exposure/adverse effects Female Humans Male Mice Mice, Hairless Mitochondria/genetics,metabolism,pathology Mitochondrial Membrane Transport Proteins/antagonists & inhibitors,genetics,metabolism Mitochondrial Permeability Transition Pore Mutation/drug effects,radiation effects Neoplasms, Radiation-Induced/drug therapy,genetics,metabolism,pathology Poly(ADP-ribose) Polymerases/genetics,metabolism Proliferating Cell Nuclear Antigen/genetics,metabolism Protein Transport/drug effects,genetics,radiation effects Pyrimidines/pharmacology,therapeutic use Skin Neoplasms/drug therapy,genetics,metabolism Tumor Suppressor Protein p53/genetics,metabolism Ultraviolet Rays/adverse effects bcl-X Protein/genetics,metabolism
Chemicals
BCL2L1 protein, human Bcl2l1 protein, mouse Cyclin D Cyclins Mitochondrial Membrane Transport Proteins Mitochondrial Permeability Transition Pore Proliferating Cell Nuclear Antigen Pyrimidines Tumor Suppressor Protein p53 bcl-X Protein Cytochromes c Poly(ADP-ribose) Polymerases Casp3 protein, mouse Caspase 3 CP 31398
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Tang Xiuwei
Department of Dermatology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Zhu Yucui
Han Lydia
Kim Arianna L
Kopelovich Levy
Bickers David R
Athar Mohammad
References (61)
61 references, click to expand
  1. Analysis of the p53 gene in human precancerous actinic keratosis lesions and squamous cell cancers.
    Cancer Lett. 1994 Sep 30;85(1):23-9 PMID: 7923098
  2. Effects of PRIMA-1 on chronic lymphocytic leukaemia cells with and without hemizygous p53 deletion.
    Br J Haematol. 2004 Nov;127(3):285-91 PMID: 15491287
  3. Restoration of p53 function leads to tumour regression in vivo.
    Nature. 2007 Feb 8;445(7128):661-5 PMID: 17251932
  4. Cancer genes and the pathways they control.
    Nat Med. 2004 Aug;10(8):789-99 PMID: 15286780
  5. J-aggregate formation of a carbocyanine as a quantitative fluorescent indicator of membrane potential.
    Biochemistry. 1991 May 7;30(18):4480-6 PMID: 2021638
  6. Regulation of p53 downstream genes.
    Semin Cancer Biol. 1998;8(5):345-57 PMID: 10101800
  7. Spectral and dose dependence of ultraviolet radiation-induced immunosuppression.
    Front Biosci. 2006 Jan 01;11:394-411 PMID: 16146741
  8. Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells.
    J Biol Chem. 1999 Dec 3;274(49):34924-31 PMID: 10574967
  9. Small molecules that reactivate mutant p53.
    Eur J Cancer. 2003 Sep;39(13):1828-34 PMID: 12932659
  10. Tumor suppressor gene therapy.
    Methods Mol Biol. 2003;223:577-98 PMID: 12777752
  11. Status of the p53 tumor suppressor gene in human squamous carcinoma cell lines.
    Oncol Res. 1992;4(8-9):349-57 PMID: 1486218
  12. UV-induced DNA damage and mutations in Hupki (human p53 knock-in) mice recapitulate p53 hotspot alterations in sun-exposed human skin.
    Cancer Res. 2001 Nov 15;61(22):8158-63 PMID: 11719445
  13. Mutations in cancer genes of UV-induced skin tumors of hairless mice.
    J Epidemiol. 1999 Dec;9(6 Suppl):S58-65 PMID: 10709351
  14. p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase.
    Cancer Res. 2005 May 1;65(9):3745-50 PMID: 15867370
  15. Cyclosporin A does not protect the disruption of the inner mitochondrial membrane potential induced by potassium ionophores in intact K562 cells.
    Cell Biol Int. 2006 Mar;30(3):197-204 PMID: 16376584
  16. Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide.
    J Am Chem Soc. 2007 Mar 7;129(9):2456-7 PMID: 17284038
  17. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound.
    Nat Med. 2002 Mar;8(3):282-8 PMID: 11875500
  18. Dose-dependent effects of UVB-induced skin carcinogenesis in hairless p53 knockout mice.
    Mutat Res. 2005 Apr 1;571(1-2):81-90 PMID: 15748640
  19. Differential response between the p53 ubiquitin-protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells.
    Exp Cell Res. 2006 Oct 15;312(17):3370-8 PMID: 16934800
  20. Restoring p53-dependent tumor suppression.
    Cancer Biol Ther. 2003 Jul-Aug;2(4 Suppl 1):S55-63 PMID: 14508081
  21. Characterization of the p53-rescue drug CP-31398 in vitro and in living cells.
    Oncogene. 2002 Mar 28;21(14):2119-29 PMID: 11948395
  22. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
    Science. 2004 Feb 6;303(5659):844-8 PMID: 14704432
  23. p53 has a direct apoptogenic role at the mitochondria.
    Mol Cell. 2003 Mar;11(3):577-90 PMID: 12667443
  24. The biology of the (6-4) photoproduct.
    Photochem Photobiol. 1989 Jun;49(6):805-19 PMID: 2672059
  25. Transactivational and DNA binding abilities of endogenous p53 in p53 mutant cell lines.
    Oncogene. 1994 Jul;9(7):1899-906 PMID: 8208536
  26. JC-1, a sensitive probe for a simultaneous detection of P-glycoprotein activity and apoptosis in leukemic cells.
    Cytometry B Clin Cytom. 2006 May;70(3):189-96 PMID: 16568474
  27. CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death.
    Oncogene. 2003 Nov 13;22(51):8233-45 PMID: 14614447
  28. Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription.
    Cancer Cell. 2003 Nov;4(5):371-81 PMID: 14667504
  29. Stage-specific alterations of cyclin expression during UVB-induced murine skin tumor development.
    Photochem Photobiol. 2002 Jan;75(1):58-67 PMID: 11837328
  30. Cell type and DNA damage specific response of human skin cells to environmental agents.
    Mutat Res. 2007 Jan 3;614(1-2):37-47 PMID: 16879839
  31. Reactive oxygen species-producing site in radiation-induced apoptosis of human peripheral T cells: involvement of lysosomal membrane destabilization.
    Int J Mol Med. 2004 Jan;13(1):69-73 PMID: 14654973
  32. The p53 tumour suppressor gene.
    Nature. 1991 Jun 6;351(6326):453-6 PMID: 2046748
  33. The p53 stabilizing compound CP-31398 induces apoptosis by activating the intrinsic Bax/mitochondrial/caspase-9 pathway.
    Exp Cell Res. 2002 Jun 10;276(2):214-22 PMID: 12027451
  34. Dissecting p53-dependent apoptosis.
    Cell Death Differ. 2006 Jun;13(6):994-1002 PMID: 16543937
  35. The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein.
    Cancer Biol Ther. 2002 Jan-Feb;1(1):47-55 PMID: 12174820
  36. Mitochondrial membrane potential in single living adult rat cardiac myocytes exposed to anoxia or metabolic inhibition.
    J Physiol. 1995 Jul 1;486 ( Pt 1):1-13 PMID: 7562625
  37. UV damage, DNA repair and skin carcinogenesis.
    Front Biosci. 2002 Apr 01;7:d1024-43 PMID: 11897551
  38. Acridine derivatives activate p53 and induce tumor cell death through Bax.
    Cancer Biol Ther. 2005 Aug;4(8):893-8 PMID: 16177561
  39. In vivo mitochondrial p53 translocation triggers a rapid first wave of cell death in response to DNA damage that can precede p53 target gene activation.
    Mol Cell Biol. 2004 Aug;24(15):6728-41 PMID: 15254240
  40. [Tumor suppressor gene p53 and molecular targeting therapy].
    Gan To Kagaku Ryoho. 2004 Sep;31(9):1309-13 PMID: 15446548
  41. Cell cycle control as a basis for cancer drug development (Review).
    Int J Oncol. 2000 May;16(5):871-86 PMID: 10762622
  42. TP53 mutations in human skin cancers.
    Hum Mutat. 2003 Mar;21(3):217-28 PMID: 12619107
  43. Wild-type p53: tumors can't stand it.
    Cell. 2007 Mar 9;128(5):837-40 PMID: 17350571
  44. P53: an ubiquitous target of anticancer drugs.
    Int J Cancer. 2002 Mar 10;98(2):161-6 PMID: 11857402
  45. Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding.
    Mol Cell Biol. 2003 Mar;23(6):2171-81 PMID: 12612087
  46. Oncology. Recruiting the cell's own guardian for cancer therapy.
    Science. 2007 Mar 2;315(5816):1211-3 PMID: 17332387
  47. Targeting p53 by PTD-mediated transduction.
    Trends Biotechnol. 2004 Sep;22(9):431-4 PMID: 15331219
  48. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation.
    Cell. 2003 Mar 21;112(6):779-91 PMID: 12654245
  49. Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1.
    Proc Natl Acad Sci U S A. 1991 May 1;88(9):3671-5 PMID: 2023917
  50. Small-molecule modulators of p53 family signaling and antitumor effects in p53-deficient human colon tumor xenografts.
    Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):11003-8 PMID: 16835297
  51. Mutant p53 melanoma cell lines respond differently to CP-31398-induced apoptosis.
    Br J Dermatol. 2005 Nov;153(5):900-10 PMID: 16225598
  52. Small peptides activate the latent sequence-specific DNA binding function of p53.
    Cell. 1995 Oct 20;83(2):237-45 PMID: 7585941
  53. Novel approaches to chemoprevention of skin cancer.
    J Dermatol. 2000 Nov;27(11):691-5 PMID: 11138532
  54. Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling.
    Cell Death Differ. 2001 Nov;8(11):1066-75 PMID: 11687885
  55. Mitochondrial permeability transition as a source of superoxide anion induced by the nitroaromatic drug nimesulide in vitro.
    Free Radic Biol Med. 2005 Oct 1;39(7):949-59 PMID: 16140214
  56. Pharmacological rescue of mutant p53 conformation and function.
    Science. 1999 Dec 24;286(5449):2507-10 PMID: 10617466
  57. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.
    Nature. 2007 Feb 8;445(7128):656-60 PMID: 17251933
  58. UVB-induced mutations in human key gatekeeper genes governing signalling pathways and consequences for skin tumourigenesis.
    Photochem Photobiol Sci. 2003 Aug;2(8):825-34 PMID: 14521217
  59. Surfing the p53 network.
    Nature. 2000 Nov 16;408(6810):307-10 PMID: 11099028
  60. Contributions of human tumor xenografts to anticancer drug development.
    Cancer Res. 2006 Apr 1;66(7):3351-4, discussion 3354 PMID: 16585151
  61. A role for neutrophil elastase in solar elastosis.
    Ciba Found Symp. 1995;192:338-46; discussion 346-7 PMID: 8575266
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI32481
Published
2007-12-00
Pages
3753-64
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2096455
Subset
IM
Grants
NCI NIH HHS · N01CN43300 · United States
NCI NIH HHS · R01 CA097249 · United States
NCI NIH HHS · N01-CN-43300 · United States
NCI NIH HHS · CA097249 · United States
NIEHS NIH HHS · R01 ES015323 · United States
NCI NIH HHS · N01-CN-35109 · United States
NCI NIH HHS · N01-CN-35105 · United States
NCI NIH HHS · N01CN35105 · United States
NCI NIH HHS · N01CN35109 · United States
NCI NIH HHS · R01 CA105136 · United States
NIAMS NIH HHS · K01 AR048582 · United States
NCI NIH HHS · R03 CA125855 · United States
Corrections
CommentIn
PMID: 18060027
External Links
PubMed source DOI: 10.1172/JCI32481 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2