Article

Autophagy Suppresses Tumorigenesis through Elimination of p62

University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Cell (Impact Factor: 33.12). 07/2009; 137(6):1062-75. DOI: 10.1016/j.cell.2009.03.048
Source: PubMed

ABSTRACT Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulated p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-kappaB regulation and gene expression and to promote tumorigenesis. Thus, defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis.

3 Followers
 · 
230 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The DAXX transcriptional repressor was originally associated with apoptotic cell death. However, recent evidence that DAXX represses several tumor suppressor genes, including the DAPK1 and DAPK3 protein kinases, and is upregulated in many cancers argues that a pro-survival role may predominate in a cancer context. Here, we report that DAXX has potent growth-enhancing effects on primary prostatic malignancy through inhibition of autophagy. Through stable gene knockdown and mouse subcutaneous xenograft studies, we demonstrate that DAXX promotes tumorigenicity of human ALVA-31 and PC3 prostate cancer (PCa) cells in vivo. Importantly, DAXX represses expression of essential autophagy modulators DAPK3 and ULK1 in vivo, revealing autophagy suppression as a mechanism through which DAXX promotes PCa tumorigenicity. Furthermore, DAXX knockdown increases autophagic flux in cultured PCa cells. Finally, interrogation of the OncomineTM database suggests that DAXX overexpression is associated with malignant transformation in several human cancers, including prostate and pancreatic cancers. Thus, DAXX may represent a new cancer biomarker for detection of aggressive disease, whose tissue-specific downregulation can serve as an improved therapeutic modality. Our results establish DAXX as a pro-survival protein in PCa, and reveal that, in the early stages of tumorigenesis, autophagy suppresses prostate tumor formation. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 04/2015; 74(19 Supplement). DOI:10.1074/jbc.M115.658765 · 4.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cholestasis is characterized by an abnormal accumulation of bile acids and causes hepatocellular injury. Recent studies show that autophagy is involved in the pathophysiology of many liver diseases. The potential role of autophagy in preventing cholestatic hepatotoxicity, however, has rarely been investigated. The aim of this study was to examine whether autophagy is involved in the cholestatic hepatotoxicity. We found that bile duct ligation (BDL) led to cholestatic liver injury and hepatocytic autophagy activation in the mice. Suppression of autophagy with Chloroquine (CQ) increased liver injury and hepatocytes apoptosis; while activation of autophagy by rapamycin reduced cholestasis hepatotoxicity. In L02 normal liver cells, Glycochenodeoxycholate (GCDC) treatment would induce autophagy. Inhibition of autophagy by CQ could promote GCDC-induced cell apoptosis. In contrast, rapamycin treatment could protect against GCDC-induced cell death. Furthermore, autophagy contributed to the liver cells survival via modulation of reactive oxygen species (ROS). These findings indicate that autophagy protects against cholestasis induced liver injury and hepatocyte apoptosis by eliminating ROS accumulation. Our data suggest that enhancement of autophagy may be a therapeutic strategy to mitigate cholestatic liver injury.
    08/2014; 4:47. DOI:10.1186/2045-3701-4-47
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypopharyngeal squamous cell carcinoma (HSCC) has the worst prognosis among head and neck cancers. Cisplatin (DDP)-based chemotherapy is an important part of multimodal treatments. However, resistance to DDP severely impairs the effectiveness of chemotherapy for HSCC. Chloroquine (CQ) has been reported to enhance the effectiveness of chemotherapy and radiotherapy in liver, pancreas, breast, prostate and colon tumors, but it is unclear whether CQ could increase the efficacy of DDP for treating HSCC. We inoculated BALB/c nude mice with a subcutaneous injection of human hypopharyngeal FaDu cells to generate our animal model. Mice were randomly divided into 4 groups and treated with vehicle control, CQ (60 mg/kg/day), DDP (5 mg/kg/6 days), or a combination of DDP and CQ. Tumor growth and survival of the mice were monitored. We found that CQ inhibited autophagy and increased DDP-induced apoptosis in the xenograft mouse model. CQ enhanced the efficacy of DDP, resulting in decreased tumor growth and prolonged survival of the mice. To test whether blocking autophagy enhanced the efficacy of DDP, FaDu cells were infected with lentiviral shRNA to Beclin-1 and inoculated into the flanks of nude mice. Inhibition of autophagy markedly enhanced the DDP-induced antitumor effect. Our study suggests that the addition of CQ to DDP-based chemotherapy could be a potential therapeutic strategy for treating HSCC, and the inhibition of autophagy may contribute to chemotherapy sensitization in HSCC.
    PLoS ONE 04/2015; 10(4):e0126147. DOI:10.1371/journal.pone.0126147 · 3.53 Impact Factor

Preview

Download
8 Downloads
Available from