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: 32.24). 07/2009; 137(6):1062-75. DOI: 10.1016/j.cell.2009.03.048
Source: PubMed


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.

40 Reads
  • Source
    • "Autophagy could also activate NF-kB to mediate pro-survival signals in fibrosarcoma cells via p38 (Cheng et al., 2009). Defective autophagy has also been reported to suppress NF-kB in the liver (Mathew et al., 2009). Although it is well perceived that autophagy is a potent suppressor of inflammation (Green et al., 2011; Latz et al., 2013), emerging data from other investigators together with ours highlights that autophagy could in certain circumstances mediate NF-kB activation and the release of pro-inflammatory cytokines. "
    [Show abstract] [Hide abstract]
    ABSTRACT: HBV and one of its encoded proteins, HBV X protein (HBx), have been shown to induce autophagy in hepatoma cells. Substantial evidence indicates that autophagy is a potent suppressor of inflammation. However, sporadic reports suggest that autophagy could promote pro-inflammatory cytokine expression and inflammation in some biological contexts. Here we show that overexpression of HBx induces LC3B-positive autophagosome formation, increases autophagic flux and enhances the expression of ATG5, ATG7, and LC3B-II in normal hepatocytes. Abrogation of autophagy by small interfering RNA against ATG5 and ATG7 prevents HBx-induced formation of autophagosomes. Autophagy inhibition also abrogates HBx-induced activation of nuclear factor-κB and production of interleukin-6 (IL-6), IL-8 and CXCL2. These findings suggest that autophagy is required for HBx-induced nuclear factor-κB activation and pro-inflammatory cytokine production and could shed new light on the complex role of autophagy in the modulation of inflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 02/2015; 230(10). DOI:10.1002/jcp.24967 · 3.84 Impact Factor
  • Source
    • "Immunoblotting analysis revealed specific increases in expression levels of the microtubule-associated protein 1 light chain 3 (LC3), a marker of autophagy [32], and Beclin 1, a protein that participates in doublemembrane autophagosome formation [33]. We also monitored the expression level of p62, an important LC3 interactor under autophagy stimulation [34] [35]. We found that the loss of p62 following PsA treatment . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Psammaplin A (PsA) is a natural product isolated from marine sponges, which has been demonstrated to have anticancer activity against several human cancer cell lines via the induction of cell cycle arrest and apoptosis. New drugs that are less toxic and more effective against multidrug-resistant cancers are urgently needed. We tested cell proliferation, cell cycle progression and autophagic cell death pathway in doxorubicin-resistant MCF-7 (MCF-7/adr) human breast cancer cells. The potency of PsA was further determined using an in vivo xenograft model. PsA significantly inhibited MCF-7/adr cells proliferation in a concentration-dependent manner, with accumulation of cells in G2/M phase of the cell cycle. PsA significantly decreased SIRT1 enzyme activity and reduced expression of SIRT1 protein in the cultured cells with greater potency than sirtinol or salermide. Acetylation of p53, a putative target of SIRT1, increased significantly following PsA treatment. In addition, PsA markedly increased the expression levels of autophagy-related proteins. In support of this, it was found that PsA significantly increased the expression of damage-regulated autophagy modulator (DRAM), a p53-induced protein. The results of this study suggest that PsA is sufficient to overcome multidrug-resistant cancer via SIRT1-mediated autophagy in MCF-7/adr breast cancer cells, indicating that PsA has therapeutic potential for clinical use. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - General Subjects 11/2014; 1850(2):401-410. DOI:10.1016/j.bbagen.2014.11.007 · 4.38 Impact Factor
  • Source
    • "Additionally given that mitochondrial DNA mutations are also incited by mitochondrial ROS production, mitophagy may be a mechanism to decrease the rate of mtDNA mutations, which may be further propagated to daughter cells and could contribute to cancer progression (Chatterjee et al., 2006). In more advanced tumors, autophagy provides energy for accelerated tumor cell growth and helps tumor cells to withstand metabolic stress (Degenhardt et al., 2006; Mathew et al., 2009; Rabinowitz & White, 2010). Moreover, the dynamic and contextual role of autophagy in cancer appears to be closely linked to the genetic landscape of the developing tumors, as recently shown in a mouse model of pancreatic ductal adenocarcinoma, where the pro-tumorigenic role of autophagy was dependent on the presence of tumor suppressor p53 (Rosenfeldt et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy, or self-eating, is the most extensively studied lysosomal degradation pathway for the recycling of obsolete or damaged cytoplasmic materials, including proteins and organelles. Although this pathway was initially thought to function as trafficking system for ‘in bulk’ degradation by the lysosomes of cytoplasmic material, it is now widely appreciated that cargo selection by the autophagic machinery is a major process underlying the cytoprotective or –possibly- pro-death functions ascribed to this catabolic process. Indeed increasing evidence suggests that in mammalian cells the removal of dysfunctional or aged mitochondria occurs through a selective degradation pathway known as ‘mitophagy’. Due to the crucial role of mitochondria in energy metabolism, redox control and cell survival/death decision, deregulated mitophagy can potentially impact a variety of crucial cell autonomous and non-autonomous processes. Accumulating evidence indicates that during malignant transformation aggressive cancers hijack autophagy to preserve energy fitness and to acquire the plasticity required to adapt to the hostile microenvironment. However, whether and how mitophagy contributes to carcinogenesis, which pathways regulates this process in the cancer cells and how cancer cell-mitophagy impacts and modifies the tumor microenvironment and therapeutic responses, remain largely unanswered issues. In this review, we discuss novel paradigms and pathways regulating mitophagy in mammalian cells and the impact this process might have on one of the most dreadful human malignancies, melanoma.
    Mitochondrion 11/2014; 19. DOI:10.1016/j.mito.2014.07.003 · 3.25 Impact Factor
Show more


40 Reads
Available from