Autophagy modulation as a potential therapeutic target for diverse diseases

Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 08/2012; 11(9):709-30. DOI: 10.1038/nrd3802
Source: PubMed

ABSTRACT Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles. It begins when double-membraned autophagosomes engulf portions of the cytoplasm, which is followed by fusion of these vesicles with lysosomes and degradation of the autophagic contents. In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. This article provides an overview of the mechanisms and regulation of autophagy, the role of this pathway in disease and strategies for therapeutic modulation.

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Available from: David C Rubinsztein, Sep 29, 2015
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    • "In response to cellular stress, such as nutrient depletion (e.g., of amino acids), TORC1 is inactivated (Loewith and Hall, 2011) and autophagy is strongly induced. Deregulation of autophagic processes is implicated in metabolic and infectious diseases as well as in cancer or neurodegeneration (Rubinsztein et al., 2012). Once induced, the autophagic machinery begins to sequester cytoplasmic components, *For correspondence: david. "
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    ABSTRACT: The degradation and recycling of cellular components is essential for cell growth and survival. Here we show how selective and non-selective lysosomal protein degradation pathways cooperate to ensure cell survival upon nutrient limitation. A quantitative analysis of starvation-induced proteome remodeling in yeast reveals comprehensive changes already in the first three hours. In this period, many different integral plasma membrane proteins undergo endocytosis and degradation in vacuoles via the multivesicular body (MVB) pathway. Their degradation becomes essential to maintain critical amino acids levels that uphold protein synthesis early during starvation. This promotes cellular adaptation, including the de novo synthesis of vacuolar hydrolases to boost the vacuolar catabolic activity. This order of events primes vacuoles for the efficient degradation of bulk cytoplasm via autophagy. Hence, a catabolic cascade including the coordinated action of the MVB pathway and autophagy is essential to enter quiescence to survive extended periods of nutrient limitation.
    eLife Sciences 04/2015; 4(4). DOI:10.7554/eLife.07736 · 9.32 Impact Factor
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    • "However, while the pro-survival function of autophagy may enable cancer cells to adapt to a hostile environment and resist cancer therapy, emerging evidence supports a highly dynamic and context dependent role for autophagy in cancer (Rosenfeldt & Ryan, 2011; Rubinsztein et al., 2012; White, 2012). In early stages of tumorigenesis, damage mitigation by autophagy serves as a tumor suppressor mechanism, limiting ROS-driven genomic instability and preventing necrosis-associated inflammation (Bray et al., 2012; Degenhardt et al., 2006; Mathew et al., 2009). "
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    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
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    • "Autophagy represents an adaptive strategy through which cells clear damaged proteins or organelles through lysosomal degradation , thus surviving from many stresses [27] [28] [29]. At the same time, autophagy also plays a vital role in the survival of cells resistant to apoptosis when they are deprived of extracellular nutrients or growth factors [30]. "
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    ABSTRACT: Pancreatic cancer remains fatal to the fast majority of affected patients. Activation of phosphoinositide-3 kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway plays an important role in pancreatic cancer progression and chemo-resistance. In the present study, we examined the activity of GDC-0980, a novel class I PI3K/mTOR kinase inhibitor, against pancreatic cancer cells in vitro. GDC-0980 inhibited AKT-mTOR activation and pancreatic cancer cell (PANC-1 and Capan-1 lines) survival. In both cancer cell lines, GDC-0980 simultaneously activated apoptosis and autophagy, the latter was detected by p62 degradation, Beclin-1 upregulation and light chain 3B (LC3B) conversion from a cytosolic (LC3B-I) to a membrane-bound (LC3B-II) form. Autophagy inhibitors including 3-methyladenine, hydroxychloroquine, NH4Cl and bafilomycin A1 enhanced apoptosis and cytotoxicity by GDC-0980, such an effect was reversed by caspase inhibitors (z-VAD-FMK and z-ITED-FMK). Furthermore, knockdown of LC3B or Beclin-1 through siRNA increased GDC-0980-induced anti-pancreatic cancer cell activity. Thus, inhibition of autophagy sensitizes GDC-0980-induced anti-pancreatic cancer activity, suggesting a novel therapeutic strategy for GDC-0980 sensitization.
    Biochemical and Biophysical Research Communications 10/2014; 453(3). DOI:10.1016/j.bbrc.2014.09.115 · 2.30 Impact Factor
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