Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis
Kirsteen H. Maclean, Frank C. Dorsey, John L. Cleveland, Michael B. Kastan
Kirsteen H. Maclean, Frank C. Dorsey, John L. Cleveland, Michael B. Kastan
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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 3

CQ is a p53-dependent chemoprevention agent.

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CQ is a p53-dependent chemoprevention agent. (A) CQ induces cell death i...
(A) CQ induces cell death in wild-type, Atm- and Arf-deficient MEFs, but not in p53-deficient MEFs. Early passage (p2) MEFs paired wild-type, Atm–/–, Arf–/–, and p53–/– MEFs were left untreated or were treated with CQ (50 μM) for 24 h. The percentage cell death was determined by staining cells with propidium iodide. Results shown are the mean of 3 independent experiments. (B) Administration of CQ i.p. impairs thymoma development in Atm-deficient mice. Beginning at weaning, Atm–/– mice were treated with 3.5 mg/kg CQ (in PBS) i.p. every 5 days, or with PBS alone (n = 20 for each group). Median survival time was 147 days for mice treated with PBS versus 254 days for mice receiving CQ (P < 0.0001). (C) Administration of CQ i.p. does not affect thymoma development in p53-deficient mice. At weaning, p53–/– mice were treated with 3.5 mg/kg CQ (in PBS) i.p. every 5 days, or with PBS alone (n = 20 for each group). Median survival time was 198 days for mice in both groups.