Role of autophagy in cancer

doi:10.1038/NRC2254

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Role of autophagy in cancer

Journal Article•DOI•

Role of autophagy in cancer

Robin Mathew¹, Vassiliki Karantza-Wadsworth¹, Eileen White•Institutions (1)

University of Medicine and Dentistry of New Jersey¹

01 Dec 2007-Nature Reviews Cancer (Nature Publishing Group)-Vol. 7, Iss: 12, pp 961-967

TL;DR: Evidence suggests that autophagy provides a protective function to limit tumour necrosis and inflammation, and to mitigate genome damage in tumour cells in response to metabolic stress.

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Abstract: Autophagy is a cellular degradation pathway for the clearance of damaged or superfluous proteins and organelles. The recycling of these intracellular constituents also serves as an alternative energy source during periods of metabolic stress to maintain homeostasis and viability. In tumour cells with defects in apoptosis, autophagy allows prolonged survival. Paradoxically, autophagy defects are associated with increased tumorigenesis, but the mechanism behind this has not been determined. Recent evidence suggests that autophagy provides a protective function to limit tumour necrosis and inflammation, and to mitigate genome damage in tumour cells in response to metabolic stress.

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Journal Article•DOI•

Hallmarks of cancer: the next generation.

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Douglas Hanahan¹, Robert A. Weinberg²•Institutions (2)

ISREC¹, Massachusetts Institute of Technology²

04 Mar 2011-Cell

TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

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51,099 citations

Cites background from "Role of autophagy in cancer"

...Perhaps paradoxically, nutrient starvation, radiotherapy, and certain cytotoxic drugs can induce elevated levels of autophagy that are apparently cytoprotective for cancer cells, impairing rather than accentuating the killing actions of these stressinducing situations (White and DiPaola, 2009; Apel et al., 2009; Amaravadi and Thompson, 2007; Mathew et al., 2007)....
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...For example, the signaling pathway involving the PI3kinase, AKT, and mTOR kinases, which is stimulated by survival signals to block apoptosis, similarly inhibits autophagy; when survival signals are insufficient, the PI3K signaling pathway is downregulated, with the result that autophagy and/or apoptosis may be induced (Levine and Kroemer, 2008; Sinha and Levine, 2008; Mathew et al., 2007)....
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...…by survival signals to block apoptosis, similarly inhibits autophagy; when survival signals are insufficient, the PI3K signaling pathway is downregulated, with the result that autophagy and/or apoptosis may be induced (Levine and Kroemer, 2008; Sinha and Levine, 2008; Mathew et al., 2007)....
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...…cytotoxic drugs can induce elevated levels of autophagy that are apparently cytoprotective for cancer cells, impairing rather than accentuating the killing actions of these stressinducing situations (White and DiPaola, 2009; Apel et al., 2009; Amaravadi and Thompson, 2007; Mathew et al., 2007)....
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Journal Article•DOI•

Autophagy in the Pathogenesis of Disease

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Beth Levine¹, Guido Kroemer², Guido Kroemer³, Guido Kroemer⁴•Institutions (4)

University of Texas Southwestern Medical Center¹, University of Paris-Sud², French Institute of Health and Medical Research³, Institut Gustave Roussy⁴

11 Jan 2008-Cell

TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.

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6,301 citations

Cites background from "Role of autophagy in cancer"

...Autophagy (from the Greek, “auto” oneself, “phagy” to eat) refers to any cellular degradative pathway that involves the delivery of cytoplasmic cargo to the lysosome....
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...Autophagy and Cancer In the past decade, several genetic links have emerged between autophagy defects and cancer, providing increasing support for the concept that autophagy is a bona fide tumor suppressor pathway (Levine, 2007; Mathew et al., 2007a)....
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...Further, immortalized kidney and mammary epithelial cells derived from beclin 1 heterozygous-deficient mice are more tumorigenic than those derived from wild-type mice (Karantza-Wadsworth et al., 2007; Mathew et al., 2007b)....
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...Autophagy May Be a Guardian of the Genome Recent studies in ATG gene-deficient immortalized epithelial cells indicate that the autophagic machinery can limit DNA damage and chromosomal instability (Mathew et al., 2007a)....
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...Second, ATG gene deletion may promote genomic instability in metabolically stressed cells, leading to oncogene activation and tumor progression (Mathew et al., 2007a)....
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Journal Article•DOI•

Autophagy fights disease through cellular self-digestion

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Noboru Mizushima¹, Beth Levine², Ana Maria Cuervo³, Daniel J. Klionsky⁴•Institutions (4)

Tokyo Medical and Dental University¹, University of Texas at Dallas², Yeshiva University³, University of Michigan⁴

28 Feb 2008-Nature

TL;DR: Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health, and to play a role in cell death.

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Abstract: Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

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5,831 citations

Journal Article•DOI•

Blinded by the Light: The Growing Complexity of p53

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Karen H. Vousden, Carol Prives¹•Institutions (1)

Columbia University¹

01 May 2009-Cell

TL;DR: Control of p53's transcriptional activity is crucial for determining which p53 response is activated, a decision that must be understood if the next generation of drugs that selectively activate or inhibit p53 are to be exploited efficiently.

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2,775 citations

Cites background from "Role of autophagy in cancer"

...…autophagy through the induction of lysosomal proteins such as DRAM (damage-regulated autophagy modulator) (Crighton et al., 2006) or through negative regulation of mTOR signaling is certainly consistent with an observed role for autophagy in tumor suppression (Matthew et al., 2007) (Figure 1)....
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Journal Article•DOI•

Repertoires of Autophagy in the Pathogenesis of Ocular Diseases

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Yu-Jie Li¹, Qin Jiang, Guo-Fan Cao, Jin Yao, Biao Yan - Show less +1 more•Institutions (1)

Nanjing Medical University¹

01 Apr 2015-Cellular Physiology and Biochemistry

TL;DR: In this manuscript, the relevant progress about the role of autophagy in the pathogenesis of ocular diseases is reviewed and pharmacological manipulation of Autophagy may provide an alternative therapeutic target for some Ocular diseases.

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Abstract: Autophagy is an important intracellular degradative process that delivers cytoplasmic proteins to lysosome for degradation. Dysfunction of autophagy is implicated in several human diseases, such as neurodegenerative diseases, infectious diseases, and cancers. Autophagy-related proteins are constitutively expressed in the eye. Increasing studies have revealed that abnormal autophagy is an important pathological feature of several ocular diseases. Pharmacological manipulation of autophagy may provide an alternative therapeutic target for some ocular diseases. In this manuscript, we reviewed the relevant progress about the role of autophagy in the pathogenesis of ocular diseases.

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2,571 citations

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References

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Journal Article•DOI•

Autophagy in the Pathogenesis of Disease

[...]

Beth Levine¹, Guido Kroemer², Guido Kroemer³, Guido Kroemer⁴•Institutions (4)

University of Texas Southwestern Medical Center¹, University of Paris-Sud², French Institute of Health and Medical Research³, Institut Gustave Roussy⁴

11 Jan 2008-Cell

TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.

...read moreread less

6,301 citations

"Role of autophagy in cancer" refers background in this paper

...Autophagy deficiency is thought to contribute to the pathogenicity in many diseases including neurodegenerative diseases, liver disease, and aging (11)....
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Journal Article•DOI•

AKT/PKB signaling: navigating downstream.

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Brendan D. Manning¹, Lewis C. Cantley²•Institutions (2)

Harvard University¹, Beth Israel Deaconess Medical Center²

29 Jun 2007-Cell

TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.

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5,505 citations

Journal Article•DOI•

Development by Self-Digestion: Molecular Mechanisms and Biological Functions of Autophagy

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Beth Levine¹, Daniel J. Klionsky²•Institutions (2)

Columbia University¹, University of Michigan²

01 Apr 2004-Developmental Cell

TL;DR: This review summarizes the current knowledge about the molecular machinery of autophagy and the role of the autophagic machinery in eukaryotic development and identifies a set of evolutionarily conserved genes that are essential forAutophagy.

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3,721 citations

Journal Article•DOI•

Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

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Taichi Hara¹, Kenji Nakamura², Makoto Matsui¹, Makoto Matsui³, Makoto Matsui⁴, Akitsugu Yamamoto⁵, Yohko Nakahara², Rika Suzuki-Migishima², Minesuke Yokoyama⁶, Kenji Mishima⁷, Ichiro Saito⁷, Hideyuki Okano⁸, Noboru Mizushima¹ - Show less +9 more•Institutions (8)

Institute of Medical Science¹, Mitsubishi², National Institute for Basic Biology, Japan³, Graduate University for Advanced Studies⁴, Nagahama Institute of Bio-Science and Technology⁵, Niigata University⁶, Tsurumi University⁷, Keio University⁸

15 Jun 2006-Nature

TL;DR: The results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

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Abstract: Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

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3,684 citations

Journal Article•DOI•

p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy

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Serhiy Pankiv¹, Terje Høyvarde Clausen¹, Trond Lamark¹, Andreas Brech², Jack-Ansgar Bruun¹, Heidi Outzen¹, Aud Øvervatn¹, Geir Bjørkøy¹, Terje Johansen¹ - Show less +5 more•Institutions (2)

University of Tromsø¹, Oslo University Hospital²

17 Aug 2007-Journal of Biological Chemistry

TL;DR: It is demonstrated that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation and p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.

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3,676 citations