Table of Contents

Volume 8, Issue 8

  August 2012

  Pages 1165 - 1280

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EDITOR'S CORNER

Open Access Article

In the beginning there was babble…

Daniel J. Klionsky, Elspeth A. Bruford, J. Michael Cherry, Jonathan Hodgkin, Stanley J.F. Laulederkind and Amy G. Singer
Pages 1165 - 1167
http://dx.doi.org/10.4161/auto.20665
Abstract | Full Text | PDF

“Go to, let us go down, and there confound their language, that they may not understand one another's speech. …Therefore is the name of it called Babel; because the Lord did there confound the language of all the earth…”

Genesis 11:7,9




AUTOPHAGIC FLUX

Highlights from this issue

Daniel J. Klionsky and Andriy Nemchenko
Page 1168
http://dx.doi.org/10.4161/auto.21836
Full Text | PDF




PERSPECTIVE

Searching for the fountain of autophagy-dependent youth: Ettore Bergamini

Daniel J. Klionsky and Ettore Bergamini
Pages 1169 - 1174
http://dx.doi.org/10.4161/auto.20788
Abstract | Full Text | PDF

One of the most exciting aspects of autophagy is its connection with aging, and the possibility of manipulating autophagy to extend life span. Many studies now demonstrate a general decrease in autophagy with age and offer some very interesting indications that reversing this trend, either genetically or pharmacologically, can have a beneficial effect with regard to aging. One of the first researchers to consider the connection between diet, aging and autophagy is Ettore Bergamini, the subject of this interview.




BASIC RESEARCH PAPERS

Immunohistochemical detection of cytoplasmic LC3 puncta in human cancer specimens

Sylvain Ladoire, Kariman Chaba, Isabelle Martins, Abdul Qader Sukkurwala, Sandy Adjemian, Mickaël Michaud, Vichnou Poirier-Colame, Felipe Andreiuolo, Lorenzo Galluzzi, Eileen White, Mathias Rosenfeldt, Kevin M. Ryan, Laurence Zitvogel and Guido Kroemer
Pages 1175 - 1184
http://dx.doi.org/10.4161/auto.20353
Abstract | Full Text | PDF

Autophagy is an evolutionarily conserved catabolic process that involves the entrapment of cytoplasmic components within characteristic vesicles for their delivery to and degradation within lysosomes. Alterations in autophagic signaling are found in several human diseases including cancer. Here, we describe a validated immunohistochemical protocol for the detection of LC3 puncta in human formalin-fixed, paraffin-embedded cancer specimens that can also be applied to mouse tissues. In response to systemic chemotherapy, autophagy-competent mouse tumors exhibited LC3 puncta, which did not appear in mouse cancers that had been rendered autophagy-deficient by the knockdown of Atg5 or Atg7. As compared with normal tissues, LC3 staining was moderately to highly elevated in the large majority of human cancers studied, albeit tumors of the same histological type tended to be highly heterogeneous in the number and intensity of LC3 puncta per cell. Moreover, tumor-infiltrating immune cells often were highly positive for LC3. Altogether, this protocol for LC3 staining appears suitable for the specific detection of LC3 puncta in human specimens, including tissue microarrays. We surmise that this technique can be employed for retrospective or prospective studies involving large series of human tumor samples.

Open Access Article

Autophagy acts as a safeguard mechanism against G-quadruplex ligand-mediated DNA damage

Nicola Ivan Orlotti, Graziella Cimino-Reale, Erika Borghini, Marzia Pennati, Claudia Sissi, Federica Perrone, Manlio Palumbo, Maria Grazia Daidone, Marco Folini and Nadia Zaffaroni
Pages 1185 - 1196
http://dx.doi.org/10.4161/auto.20519
Abstract | Full Text | PDF

G-quadruplex ligands have attracted considerable interest as novel anticancer therapeutics due to their capability to interfere with guanosine-rich DNA/RNA sequences, such as telomeres. Elucidation of the structures of telomeric G-quadruplexes has led, in the past few years, to the rational development of effective G-quadruplex-stabilizing small molecules. In the present study, we showed that short-term exposure of melanoma cells to Ant1,5—an anthracene-based ligand able to stabilize telomeric G-quadruplexes—impaired cell growth without inducing cell senescence or apoptosis. Conversely, drug-treated cells were characterized by the occurrence of typical biochemical and morphological features associated with autophagy, such as an increase in the lipidated form of the autophagic marker LC3B and the accumulation of autophagosomes. Such drug-induced autophagy occurred as a consequence of DNA damage induction, at least in part dependent on drug-mediated telomere uncapping, through a pathway converging on the cyclin-dependent kinase inhibitor 1A (CDKN1A/p21). Indeed, melanoma cells depleted for CDKN1A did not show evidence of autophagic markers upon exposure to Ant1,5. The inhibition of autophagy by a pharmacologic inhibitor or through RNAi-mediated depletion of the ATG5 gene enhanced the cytotoxic activity of Ant1,5, as revealed by the marked increase in drug-induced apoptosis. Our data outline a molecular scenario in which G-quadruplex ligand-induced telomeric dysfunctions and DNA damage are translated into an autophagic response and provide the first evidence of autophagy as a safeguard mechanism activated by melanoma cells to counteract G-quadruplex ligand-mediated cellular stress.

AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization

Hildegard I.D. Mack, Bin Zheng, John Asara and Sheila M. Thomas
Pages 1197 - 1214
http://dx.doi.org/10.4161/auto.20586
Abstract | Full Text | PDF

Autophagy is activated in response to a variety of cellular stresses including metabolic stress. While elegant genetic studies in yeast have identified the core autophagy machinery, the signaling pathways that regulate this process are less understood. AMPK is an energy sensing kinase and several studies have suggested that AMPK is required for autophagy. The biochemical connections between AMPK and autophagy, however, have not been elucidated. In this report, we identify a biochemical connection between a critical regulator of autophagy, ULK1, and the energy sensing kinase, AMPK. ULK1 forms a complex with AMPK, and AMPK activation results in ULK1 phosphorylation. Moreover, we demonstrate that the immediate effect of AMPK-dependent phosphorylation of ULK1 results in enhanced binding of the adaptor protein YWHAZ/14-3-3ζ; and this binding alters ULK1 phosphorylation in vitro. Finally, we provide evidence that both AMPK and ULK1 regulate localization of a critical component of the phagophore, ATG9, and that some of the AMPK phosphorylation sites on ULK1 are important for regulating ATG9 localization. Taken together these data identify an ULK1-AMPK signaling cassette involved in regulation of the autophagy machinery.




TOOLBOX

Open Access Article

Monitoring autophagic flux by an improved tandem fluorescent-tagged LC3 (mTagRFP-mWasabi-LC3) reveals that high-dose rapamycin impairs autophagic flux in cancer cells

Cuihong Zhou, Wu Zhong, Jun Zhou, Fugeng Sheng, Ziyuan Fang, Yue Wei, Yingyu Chen, Xiaoyan Deng, Bin Xia and Jian Lin
Pages 1215 - 1226
http://dx.doi.org/10.4161/auto.20284
Abstract | Full Text | PDF

Monitoring autophagic flux is important for the analysis of autophagy. Tandem fluorescent-tagged LC3 (mRFP-EGFP-LC3) is a convenient assay for monitoring autophagic flux based on different pH stability of EGFP and mRFP fluorescent proteins. However, it has been reported that there is still weak fluorescence of EGFP in acidic environments (pH between 4 and 5) or acidic lysosomes. So it is possible that autolysosomes are labeled with yellow signals (GFP⁺RFP⁺ puncta), which results in misinterpreting autophagic flux results. Therefore, it is desirable to choose a monomeric green fluorescent protein that is more acid sensitive than EGFP in the assay of autophagic flux. Here, we report on an mTagRFP-mWasabi-LC3 reporter, in which mWasabi is more acid sensitive than EGFP and has no fluorescence in acidic lysosomes. Meanwhile, mTagRFP-mWasabi-LC3ΔG was constructed as the negative control for this assay. Compared with mRFP-EGFP-LC3, our results showed that this reporter is more sensitive and accurate in detecting the accumulation of autophagosomes and autolysosomes. Using this reporter, we find that high-dose rapamycin (30 μM) will impair autophagic flux, inducing many more autophagosomes than autolysosomes in HeLa cells, while low-dose rapamycin (500 nM) has an opposite effect. In addition, other chemical autophagy inducers (cisplatin, staurosporine and Z18) also elicit much more autophagosomes at high doses than those at low doses. Our results suggest that the dosage of chemical autophagy inducers would obviously influence autophagic flux in cells.

Open Access Article

A quantitative TR-FRET plate reader immunoassay for measuring autophagy

Michael K. Hancock, Spencer B. Hermanson and Nicholas J. Dolman
Pages 1227 - 1244
http://dx.doi.org/10.4161/auto.20441
Abstract | Full Text | PDF

Autophagy involves the isolation and targeting of unwanted cellular components to lysosomes for their digestion and reuse. Autophagic dysregulation has recently been implicated in a wide range of disease processes, yet facile methods for quantifying autophagy have been lacking in the field. Here we describe the generation of a quantitative plate reader assay for measuring the autophagic activity of cells. One of the best characterized autophagy markers is the protein LC3B, which normally resides in the cytosol (LC3B-I) but upon induction of autophagy becomes lipidated and embedded in autophagosomal membranes (LC3B-II). To quantify autophagy, we reasoned that GFP-tagged LC3B could serve as a time-resolved fluorescence resonance energy transfer (TR-FRET) acceptor upon cell lysis in the presence of terbium-labeled LC3B antibodies. Using this TR-FRET immunoassay approach, we screened a panel of LC3B antibodies and identified an antibody that exhibits strong preferential affinity toward autophagosome-associated LC3B-II and thereby facilitates specific detection of autophagic activity. The plate reader format provides both a quantitative and an objective result, thus overcoming some of the key limitations of the traditional immunoblotting and imaging approaches used to monitor autophagy. Moreover, since the assay step requires only a single addition of cell lysis buffer containing the detection antibody its simple workflow is both automation-friendly and scalable, which renders it suitable for high-throughput screening. We demonstrate how this TR-FRET immunoassay for GFP-tagged LC3B-II can be applied to quantitatively detect changes in the autophagy activity of cells, including estimating effects on autophagic flux.




PROTOCOL

Proteinase protection of prApe1 as a tool to monitor Cvt vesicle/autophagosome biogenesis

Wei-Lien Yen and Daniel J. Klionsky
Pages 1245 - 1249
http://dx.doi.org/10.4161/auto.20916
Abstract | Full Text | PDF

Due in part to the increasing number of links between autophagy malfunction and human diseases, this field has gained tremendous attention over the past decade. Our increased understanding of the molecular machinery involved in macroautophagy (hereafter autophagy) seems to indicate that the most complex step, or at least the stage of the process where the majority of the autophagy-related (Atg) proteins participate, is in the formation of the double-membrane sequestering vesicle. Thus, it is important to establish reliable approaches to monitor this specific process. One of the most commonly used methods is morphological analysis by electron microscopy of the cytosolic vesicles used in the cytoplasm-to-vacuole targeting (Cvt) pathway and autophagy, or the single-membrane intralumenal products, termed Cvt or autophagic bodies, that are formed after the fusion of these vesicles with the yeast vacuole. This method, however, can be costly and time consuming, and reliable analysis requires expert input. Furthermore, it is extremely difficult to detect an incomplete autophagosome by electron microscopy because of the difficulty of obtaining a section that randomly cuts through the open portion of the phagophore. The primary Cvt pathway cargo, precursor amminopeptidase I (prApe1), is enwrapped within either a Cvt vesicle or autophagosome depending on the nutritional conditions. The proteolytic sensitivity of the prApe1 propeptide can therefore serve as a useful tool to determine the completion status of double-membrane Cvt vesicles/autophagosomes in the presence of exogenously added proteinase. Here, we describe an assay that examines the proteinase protection of prApe1 for determining the completion of Cvt vesicles/autophagosomes.




AUTOPHAGIC PUNCTA

Autophagy and cell death

Simone Fulda
Pages 1250 - 1251
http://dx.doi.org/10.4161/auto.20669
Abstract | Full Text | PDF

Autophagy exerts dual functions in cancer, acting as both a tumor suppressor, for example, by preventing the accumulation of damaged proteins and organelles, and as a tumor promoter that supports tumor growth. Many anticancer therapies engage autophagy as part of a cellular response. However, the question of whether or not autophagic activity in cells undergoing cell death is the cause of death or whether it is actually an attempt to support survival in response to cellular stress conditions has been discussed with great controversy.

Is reactivation of autophagy a possible therapeutic solution for obesity and metabolic syndrome?

Sebastiano Sciarretta, Massimo Volpe and Junichi Sadoshima
Pages 1252 - 1254
http://dx.doi.org/10.4161/auto.20670
Abstract | Full Text | PDF

The molecular mechanism regulating the cardiomyocyte response to energy stress has been a hot topic in cardiac research in recent years, since this mechanism could be targeted for treatment of patients with ischemic heart disease. We have shown recently that the activity of RAS homolog enriched in brain (RHEB), a small GTP binding protein, is inhibited in response to glucose deprivation (GD) in cardiomyocytes and ischemia in the mouse heart. This is a physiological adaptation, since it inhibits complex 1 of the mechanistic target of rapamycin (MTORC1) and activates autophagy, thereby promoting cell survival during GD and prolonged ischemia. Importantly, the physiological inhibition of RHEB-MTORC1 signaling during myocardial ischemia is impaired in the presence of obesity and metabolic syndrome caused by high-fat diet (HFD) feeding, leading to a dramatic increase in ischemic injury. Although MTORC1 and autophagy can be regulated through RHEB-independent mechanisms, such as the AMPK-dependent phosphorylation of RPTOR and ULK1, RHEB appears to be critical in the regulation of MTORC1 and autophagy during ischemia in cardiomyocytes, and its dysregulation is relevant to human disease. Here we discuss the biological relevance of the dysregulation of RHEB-MTORC1 signaling and the suppression of autophagy in obesity and metabolic syndrome.

Dismantling the autophagic arsenal when it is time to die: Concerted AMBRA1 degradation by caspases and calpains

Marco Corazzari, Gian Maria Fimia and Mauro Piacentini
Pages 1255 - 1257
http://dx.doi.org/10.4161/auto.20671
Abstract | Full Text | PDF

Under stress conditions cells activate different response pathways which result in cell survival or apoptosis depending on: (1) the nature of the insults, (2) the type, if acute or chronic stress, and (3) how long the stress persists. Generally, autophagy is induced early to sustain cell survival and inhibit cell death. However, adverse conditions are able to overcome autophagy to promote cell death. Increasing evidence suggests that the inhibition of autophagy by the apoptotic machinery has been proposed as one of the crucial events responsible for the irreversible switch from survival to death. The mechanism seems to be related to the selective apoptotic protease-mediated degradation of key autophagic proteins. We recently found that AMBRA1, an important regulator of the autophagic process mediating the initial steps of autophagosome formation, is also irreversibly degraded by the combined activity of caspases and calpains. This phenomenon is not merely a consequence of apoptosis execution but represents a key step required to efficiently promote the autophagic vs apoptosis switch.

The BECN1 coiled coil domain: An “imperfect” homodimer interface that facilitates ATG14 and UVRAG binding

Xiaohua Li, Liqiang He, Mingjie Zhang, Zhenyu Yue and Yanxiang Zhao
Pages 1258 - 1260
http://dx.doi.org/10.4161/auto.20750
Abstract | Full Text | PDF

The coiled-coil domain of BECN1 serves as a protein interaction platform to recruit two major autophagy regulators ATG14 and UVRAG. Our crystal structure of the BECN1 coiled-coil domain reveals a homodimer with an imperfect dimer interface. This “imperfect” feature favors the formation of a stable BECN1-ATG14 or BECN1-UVRAG heterodimer over a metastable BECN1 homodimer to promote autophagy and/or endocytic pathways.

Chikungunya-induced cell death is limited by ER and oxidative stress-induced autophagy

Pierre-Emmanuel Joubert, Scott Werneke, Claire de la Calle, Florence Guivel-Benhassine, Alessandra Giodini, Lucie Peduto, Beth Levine, Olivier Schwartz, Deborah Lenschow and Matthew L. Albert
Pages 1261 - 1263
http://dx.doi.org/10.4161/auto.20751
Abstract | Full Text | PDF

It has been recognized that macroautophagy constitutes an important survival mechanism that allows both the maintenance of cellular homeostasis and the regulation of programmed cell death pathways (e.g., apoptosis). Although several pathogens have been described to induce autophagy, the prosurvival function of this process in infectious models remains poorly characterized. Our recent studies on chikungunya virus (CHIKV), the causative agent of major epidemics in India, Southeast Asia and southern Europe, reveal a novel mechanism by which autophagy limits the cytopathic effects of CHIKV by impinging upon virus-induced cell death pathways.

Blocking the interleukin 2 (IL2)-induced systemic autophagic syndrome promotes profound antitumor effects and limits toxicity

Michael T. Lotze, William Buchser and Xiaoyan Liang
Pages 1264 - 1266
http://dx.doi.org/10.4161/auto.20752
Abstract | Full Text | PDF

Cancer is the leading cause of death in the United States in those dying under the age of 85. Although cancer is increasingly controlled as a chronic disease, true cures of patients with metastatic epithelial malignancies have rarely been obtained with currently available systemic therapies. For example, administration of high-dose recombinant interleukin 2 (IL2), enhancing cytolytic immune cell proliferation and delivery, promotes complete antitumor responses in < 10% of treated individuals. Means to reduce the toxicity, attributed to a cytokine storm and an associated “systemic autophagic syndrome” as well as enhance efficacy and increase the potential set of malignancies in which it is applied (currently patients with renal cancer and melanoma) would be of great interest. IL2 promotes both T-cell and NK cell induction of immune cell-mediated autophagy (iC-MA) in tumor targets. We have demonstrated that HMGB1 is detected at high levels in the serum of IL2-treated mice with translocation to the cytoplasm from the nucleus in the liver, consistent with HMGB1’s release in response to stress, and ability to sustain autophagy. Limiting autophagy in mice with coadministration of chloroquine (CQ) diminishes serum levels of HMGB1, cytokines (IFNG and IL6 but not IL18), and autophagic flux, attenuating weight gain, enhancing DC, T-cell and NK cell numbers, and promoting long-term tumor control in a murine hepatic metastases model. Autophagy (programmed cell survival) is a metabolic process associated with promotion of late cancer growth. In tumor cell lines, CQ treatment limits ATP production through inhibition of oxidative phosphorylation and promotion of apoptosis. CQ increases autophagic vacuoles and LC3-II levels in tumor cells, associated with increased annexin V⁺/PI^- cells, cleaved-PARP, cleaved-CASP3, and cytochrome c release from mitochondria. These observations, limiting toxicity and prolonging antitumor effects, with a combination of IL2 and autophagy inhibition in murine models are now being tested by the Cytokine Working Group in patients with advanced renal cell carcinoma.

Autophagy genes promote apoptotic cell corpse clearance

Wei Zou, Xiaochen Wang, Ronald Vale and Guangshuo Ou
Pages 1267 - 1268
http://dx.doi.org/10.4161/auto.20786
Abstract | Full Text | PDF

Autophagy is a catabolic process through which damaged organelles and protein aggregates are delivered to lysosomes for degradation. Autophagy genes are reported to promote exposure of “eat me” signals on the surface of apoptotic cells, but whether they function in engulfing cells is not clear. Recently, we found that the autophagy mutants atg-18 and epg-5 are defective in removing apoptotic cells derived from the C. elegans Q neuroblast, a phenotype that can be fully rescued by expression of ATG-18 and EPG-5 in the engulfing cell. Loss of ATG-18 or EPG-5 does not affect cell corpse engulfment but causes defects in phagosomal recruitment of RAB-5 and RAB-7 and formation of phagolysosomes. EPG-5, ATG-18 and LGG-1 are sequentially recruited to phagosomes, suggesting that they function at different steps of phagosomal maturation. Our studies indicate that autophagy genes function sequentially to promote apoptotic cell corpse degradation in the engulfing cell.

A role for the membrane Golgi protein Ema in autophagy

Sungsu Kim and Aaron DiAntonio
Pages 1269 - 1270
http://dx.doi.org/10.4161/auto.20871
Abstract | Full Text | PDF

Autophagy is a cellular homeostatic response that involves degradation of self-components by the double-membraned autophagosome. The biogenesis of autophagosomes has been well described, but the ensuing processes after autophagosome formation are not clear. In our recent study, we proposed a model in which the Golgi complex contributes to the growth of autophagic structures, and that the Drosophila melanogaster membrane protein Ema promotes this process. In fat body cells of the D. melanogaster ema mutant, the recruitment of the Golgi complex protein Lava lamp (Lva) to autophagic structures is impaired and autophagic structures are very small. In addition, in the ema mutant autophagic turnover of SQSTM1/p62 and mitophagy are impaired. Our study not only identifies a role for Ema in autophagy, but also supports the hypothesis that the Golgi complex may be a potential membrane source for the biogenesis and development of autophagic structures.

A Ypt/Rab GTPase module makes a PAS

Zhanna Lipatova and Nava Segev
Pages 1271 - 1272
http://dx.doi.org/10.4161/auto.20872
Abstract | Full Text | PDF

Organization of membrane micro-domains by Ypt/Rab GTPases is key for all membrane trafficking events in eukaryotic cells. Since autophagy is a membrane trafficking process, it was expected that these GTPases would play a role in autophagy as well. While evidence about participation of Ypt/Rabs in autophagy is beginning to emerge, the mechanisms by which they act in this process are still not clear. Moreover, it is still questionable if and how Ypt/Rabs coordinate autophagy with other cellular trafficking processes. Yeast Ypt1 and its mammalian homolog Rab1 are required for both endoplasmic reticulum (ER)-to-Golgi transport and autophagy, suggesting that they coordinate these two processes. In our recent paper, we identify Atg11, a bona fide phagophore assembly site (PAS) component, as a downstream effector of Ypt1. Moreover, we show that three components of a GTPase module—the Ypt1 activator, Trs85-containing TRAPP complex, Ypt1, and the Atg11 effector—interact on the PAS and are required for PAS formation during selective autophagy. We propose that Ypt/Rabs coordinate the secretory and the autophagic pathways by recruiting process-specific effectors.

Augmented autophagy pathways and MTOR modulation in fibroblasts from long-lived mutant mice

Min Wang and Richard A. Miller
Pages 1273 - 1274
http://dx.doi.org/10.4161/auto.20917
Abstract | Full Text | PDF

Fibroblasts from long-lived pituitary dwarf mutants, including Snell dwarf, Ames dwarf and the growth hormone receptor knockout (GHRKO) mice, are resistant in culture to multiple forms of lethal stress. We found that fibroblasts from Snell dwarf and GHRKO mice are more susceptible than control cells to autophagy induced by amino acid withdrawal or by oxidative stress. We also found evidence for lower MTOR function in dwarf cells under conditions that induce autophagy, consistent with the evidence that increased autophagy requires lower TOR activity. Our results provide new hints about the connections between autophagy and aging in long-lived mutants with alterations in GH-IGF1 levels, and suggest a role for hyperactive autophagy in the resistance of cells from these mice to lethal stresses.




VIEWS AND COMMENTARIES

Atg11: A Rab-dependent, coiled-coil membrane protein that acts as a tether for autophagy

Steven K. Backues and Daniel J. Klionsky
Pages 1275 - 1278
http://dx.doi.org/10.4161/auto.21153
Abstract | Full Text | PDF

Selective macroautophagy uses double-membrane vesicles, termed autophagosomes, to transport cytoplasmic pathogens, organelles and protein complexes to the vacuole for degradation. Autophagosomes are formed de novo by membrane fusion events at the phagophore assembly site (PAS). Therefore, precursor membrane material must be targeted and transported to the PAS. While some autophagy-related (Atg) proteins, such as Atg9 and Atg11, are known to be involved in this process, most of the mechanistic details are not understood. Previous work has also implicated the small Rab-family GTPase Ypt1 in the process, identifying Trs85 as a unique subunit of the TRAPPIII targeting complex and showing that it plays a macroautophagy-specific role; however, the relationship between Ypt1, Atg9 and Atg11 was not clear. Now, a recent report shows that Atg11 is a Trs85-specific effector of the Rab Ypt1, and may act as a classic coiled-coil membrane tether that targets Atg9-containing membranes to the PAS. Here, we review this finding in the context of what is known about Atg11, other Rab-dependent coiled-coil tethers, and other tethering complexes involved in autophagosome formation.




MEETING REPORT

Open Access Article

Targeting autophagy: The Achilles’ heel of cancer

Sharon M. Gorski, Jenna Ries and Julian J. Lum
Pages 1279 - 1280
http://dx.doi.org/10.4161/auto.20828
Abstract | Full Text | PDF

In recent years, tremendous progress has been made toward unveiling the mechanism of autophagy and its exploitation by many different cancer types. This year the American Association for the Advancement of Science held a one day Symposium on Autophagy: An Emerging Therapeutic Target in Human Disease in Vancouver, British Columbia and brought together experts in cell biology, drug discovery, and clinical translation to share their research findings and prospects. Currently, autophagy is being investigated on several fronts, from modulation of gene expression to in vivo studies, and more recently clinical trials in cancer. Key topics of discussion were determining which stage of autophagy would be the ideal target for inhibition to produce the highest impact, and which cancers or cancer subtypes would be the most sensitive to autophagy inhibitors; the answers to these questions may be a turning point in cancer therapy research.