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Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis.

Publication ,  Journal Article
Maclean, KH; Dorsey, FC; Cleveland, JL; Kastan, MB
Published in: J Clin Invest
January 2008

Despite great interest in cancer chemoprevention, effective agents are few. Here we show that chloroquine, a drug that activates the stress-responsive Atm-p53 tumor-suppressor pathway, preferentially enhances the death of Myc oncogene-overexpressing primary mouse B cells and mouse embryonic fibroblasts (MEFs) and impairs Myc-induced lymphomagenesis in a transgenic mouse model of human Burkitt lymphoma. Chloroquine-induced cell death in primary MEFs and human colorectal cancer cells was dependent upon p53, but not upon the p53 modulators Atm or Arf. Accordingly, chloroquine impaired spontaneous lymphoma development in Atm-deficient mice, a mouse model of ataxia telangiectasia, but not in p53-deficient mice. Chloroquine treatment enhanced markers of both macroautophagy and apoptosis in MEFs but ultimately impaired lysosomal protein degradation. Interestingly, chloroquine-induced cell death was not dependent on caspase-mediated apoptosis, as neither overexpression of the antiapoptotic protein Bcl-2 nor deletion of the proapoptotic Bax and Bak affected chloroquine-induced MEF death. However, when both apoptotic and autophagic pathways were blocked simultaneously, chloroquine-induced killing of Myc-overexpressing cells was blunted. Thus chloroquine induces lysosomal stress and provokes a p53-dependent cell death that does not require caspase-mediated apoptosis. These findings specifically demonstrate that intermittent chloroquine use effectively prevents cancer in mouse models of 2 genetically distinct human cancer syndromes, Burkitt lymphoma and ataxia telangiectasia, suggesting that agents targeting lysosome-mediated degradation may be effective in cancer prevention.

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

January 2008

Volume

118

Issue

1

Start / End Page

79 / 88

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • bcl-2 Homologous Antagonist-Killer Protein
  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-myc
  • Protein Serine-Threonine Kinases
  • Neoplasms, Experimental
  • Mice, Mutant Strains
  • Mice
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Maclean, K. H., Dorsey, F. C., Cleveland, J. L., & Kastan, M. B. (2008). Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest, 118(1), 79–88. https://doi.org/10.1172/JCI33700
Maclean, Kirsteen H., Frank C. Dorsey, John L. Cleveland, and Michael B. Kastan. “Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis.J Clin Invest 118, no. 1 (January 2008): 79–88. https://doi.org/10.1172/JCI33700.
Maclean KH, Dorsey FC, Cleveland JL, Kastan MB. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest. 2008 Jan;118(1):79–88.
Maclean, Kirsteen H., et al. “Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis.J Clin Invest, vol. 118, no. 1, Jan. 2008, pp. 79–88. Pubmed, doi:10.1172/JCI33700.
Maclean KH, Dorsey FC, Cleveland JL, Kastan MB. Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J Clin Invest. 2008 Jan;118(1):79–88.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

January 2008

Volume

118

Issue

1

Start / End Page

79 / 88

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • bcl-2 Homologous Antagonist-Killer Protein
  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-myc
  • Protein Serine-Threonine Kinases
  • Neoplasms, Experimental
  • Mice, Mutant Strains
  • Mice
  • Male