Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis
Kirsteen H. Maclean, … , John L. Cleveland, Michael B. Kastan
Kirsteen H. Maclean, … , John L. Cleveland, Michael B. Kastan
Published December 20, 2007
Citation Information: J Clin Invest. 2008;118(1):79-88. https://doi.org/10.1172/JCI33700.
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Research Article

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

Abstract

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.

Authors

Kirsteen H. Maclean, Frank C. Dorsey, John L. Cleveland, Michael B. Kastan

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Figure 1

CQ prevents Myc-induced lymphomagenesis.

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CQ prevents Myc-induced lymphomagenesis. (A) Administration (i.p.) of CQ...
(A) Administration (i.p.) of CQ impairs lymphoma development in Eμ-Myc transgenic mice. Beginning at weaning, Eμ-Myc mice were treated with 3.5 mg/kg CQ (in PBS) i.p. every 5 days, or with PBS alone (n = 18 for each group). Median survival time was 98 days for mice treated with PBS versus 265 days for mice receiving CQ (P = 0.0002). (B) CQ treatment prevents lymphocytosis in precancerous Eμ-Myc transgenic mice. Beginning at 4 weeks, Eμ-Myc transgenic mice and their wild-type littermates (n = 5–8 for each group) were injected with 3.5 mg/kg CQ (in PBS) i.p. every 5 days, or with PBS alone. At 7 weeks, mice were then analyzed for wbc counts. CQ had no effect on wbc numbers in wild-type mice but had profound effects on wbc numbers in Eμ-Myc mice. *P < 0.05. (C) CQ treatment prevents splenomegaly in precancerous Eμ-Myc transgenic mice. Beginning at 4 weeks, Eμ-Myc transgenic mice and their wild-type littermates (n = 8 for each group) were injected with 3.5 mg/kg CQ (in PBS) i.p. every 5 days, or injected with PBS alone. At 7 weeks, mice were then analyzed for spleen weight. Pictures in inset show representative spleens from wild-type and Eμ-Myc transgenic mice injected with PBS or CQ.