Mechanisms of Selective Autophagy in Normal Physiology and Cancer

Mancias, Joseph D.; Kimmelman, Alec C.

doi:10.1016/j.jmb.2016.02.027

Cited by 153 publications

(131 citation statements)

References 203 publications

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“…Similar to autophagy, which is shown to be both pro- and anti-tumorgenic based on context, the function of mitophagy in transformation likely depends on tumor stage (Mancias and Kimmelman, 2016). Mitophagy-deficient Parkin null mice develop spontaneous hepatic tumors, and Parkin loss increases tumorigenesis in multiple cancer models (Matsuda et al, 2015).…”

Section: Mitochondrial Biogenesis and Turnovermentioning

confidence: 99%

Mitochondria and Cancer

Vyas

Zaganjor

Haigis

2016

Cell

1,252

1,065

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Mitochondria are bioenergetic, biosynthetic and signaling organelles that are integral in stress sensing to allow for cellular adaptation to the environment. Therefore, it is not surprising that mitochondria are important mediators of tumorigenesis, as this process requires flexibility to adapt to cellular and environmental alterations in addition to cancer treatments. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation including mitochondrial biogenesis and turnover, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. Thus, understanding mechanisms of mitochondrial misregulation during tumorigenesis will be critical for the next generation of cancer therapeutics.

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Section: Mitochondrial Biogenesis and Turnovermentioning

confidence: 99%

Mitochondria and Cancer

Vyas

Zaganjor

Haigis

2016

Cell

1,252

1,065

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“…Future work will uncover the role of other cargo receptors and the six ATG8 proteins in the control of selective autophagy. Additionally, with the realization that the regulated expression of specialized cargo receptors allows the cell to promote one type of selective autophagy over another (Green and Levine 2014), it is also timely to consider how one can exploit inactivation of such selective adaptor proteins to parse out the different roles of autophagy in cancer to determine whether specific types of autophagy play more significant roles than others in tumorigenesis (Mancias and Kimmelman 2016).…”

Section: Regulation Of Core Autophagy Genes and Cargo Receptors In Camentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumorpromoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.The core autophagy machinery is encoded by autophagyrelated (ATG) genes, of which there are now >30 (Ktistakis and Tooze 2016). These genes and their protein products are regulated by numerous upstream signals, including nutrient availability, stressors, defective organelles, and pathogenic conditions. ATG gene products control the formation of the hallmark double-membrane vesicle, the autophagosome. Other genes encode cargo receptors that direct the cargo to the forming autophagosome. Control of the trafficking machinery then orchestrates fusion of the cargo-laden autophagosomes with lysosomes. Degradative enzymes, contributed by lysosomes, break down the cargo, and the products are exported into the cytoplasm, where they are recycled into metabolic and biosynthetic pathways (Rabinowitz and White 2010;Guo et al. 2016). Under normal nutrient conditions, autophagy functions at a constitutive, low basal level to maintain protein and organelle quality, quantity, and functionality. The ATG genes and autophagy are dramatically induced by starvation and other stressors, which enable cellular and organismal survival. Up-regulation of autophagy is a means to survive nutrient stress, which is conserved from yeast to mammals. More recently, there is a growing appreciation of the role played by ATG genes in modulating intracellular trafficking, endocytosis, exoc...

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“…This process involves the lipidation of ubiquitin-like ATG8 proteins (MAP1LC3A, MAP1LC3B and MAP1LC3C and GABARAP, GABARAPL1 and GABARAPL2 in mammalian cells) to promote autophagosome formation, maturation and cargo recruitment 111 . Evidence to support an increase in the number of autophagosomes and in the expression of autophagic machinery was initially observed in human colon cancer cells (HCT116) that contain supernumerary chromosomes 112 .…”

Section: Autophagy and The Control Of Proteome Imbalancementioning

confidence: 99%

Proteome complexity and the forces that drive proteome imbalance

Harper

Bennett

2016

Nature

201

175

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Summary The cellular proteome is a complex microcosm of structural and regulatory networks that requires continuous surveillance and modification to meet the dynamic needs of the cell. It is therefore crucial that the protein flux of the cell remains in balance to ensure proper cell function. Genetic alterations that range from chromosome imbalance to oncogene activation can affect the speed, fidelity and capacity of protein biogenesis and degradation systems, which often results in proteome imbalance. An improved understanding of the causes and consequences of proteome imbalance is helping to reveal how these systems can be targeted to treat diseases such as cancer.

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Mechanisms of Selective Autophagy in Normal Physiology and Cancer

Cited by 153 publications

References 203 publications

Mitochondria and Cancer

Mitochondria and Cancer

Recent insights into the function of autophagy in cancer

Proteome complexity and the forces that drive proteome imbalance

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