Context-dependent role of ATG4B as target for autophagy inhibition in prostate cancer therapy

Tran, Elisa; Chow, Annabelle; Goda, Takeshi; Wong, Amy; Blakely, Kim M.; Rocha, Michelle C.; Taeb, Samira; Hoang, Van; Liu, Stanley K.; Emmenegger, Urban

doi:10.1016/j.bbrc.2013.10.117

Cited by 34 publications

(29 citation statements)

References 33 publications

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“…55 Finally, ATG4B is an emerging target for treatment of various cancers, and inhibitors are being actively developed. 56 If the above speculations prove correct, they counsel caution in the use of such compounds, as the resulting increase in intracellular proLC3 may increase susceptibility to RNA virus infections.…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus can exploit LC3 in both autophagy-dependent and -independent manners in vivo

et al. 2015

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RNA viruses modify intracellular membranes to produce replication scaffolds. In pancreatic cells, coxsackievirus B3 (CVB3) hijacks membranes from the autophagy pathway, and in vivo disruption of acinar cell autophagy dramatically delays CVB3 replication. This is reversed by expression of GFP-LC3, indicating that CVB3 may acquire membranes from an alternative, autophagy-independent, source(s). Herein, using 3 recombinant CVB3s (rCVB3s) encoding different proteins (proLC3, proLC3 G120A , or ATG4B C74A ), we show that CVB3 is, indeed, flexible in its utilization of cellular membranes. When compared with a control rCVB3, all 3 viruses replicated to high titers in vivo, and caused severe pancreatitis. Most importantly, each virus appeared to subvert membranes in a unique manner. The proLC3 virus produced a large quantity of LC3-I which binds to phosphatidylethanolamine (PE), affording access to the autophagy pathway. The proLC3 G120A protein cannot attach to PE, and instead binds to the ER-resident protein SEL1L, potentially providing an autophagy-independent source of membranes. Finally, the ATG4B C74A protein sequestered host cell LC3-I, causing accumulation of immature phagophores, and massive membrane rearrangement. Taken together, our data indicate that some RNA viruses can exploit a variety of different intracellular membranes, potentially maximizing their replication in each of the diverse cell types that they infect in vivo.

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Section: Discussionmentioning

confidence: 99%

Coxsackievirus can exploit LC3 in both autophagy-dependent and -independent manners in vivo

et al. 2015

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“…However, the role of ATG4 proteases in most diseases is context dependent, and the consequences of their modulation could differ greatly. For example, it has been suggested that changes in the expression of ATG4B in prostate cancer could either amplify the action of both chemotherapy and radiotherapy or contribute to the development of treatment resistance (120). Furthermore, inhibition of ATG4 proteases in radiation therapies sensitizes resistant carcinoma cells in most cases, although it also promotes resistance in some conditions (121), demonstrating the importance of a more comprehensive understanding of ATG4 function.…”

Section: Therapeutic Options Targeting Atg4 Proteasesmentioning

confidence: 99%

The functional and pathologic relevance of autophagy proteases

Fernández¹,

López-Otı́n²

2015

J. Clin. Invest.

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“…There is genetic proof of principal that loss of ATG7 suppresses tumorigenesis (5), and an inhibitor might be expected to do the same. Over-expression of a dominant-negative ATG4b can either increase toxicity or promote resistance to cytotoxic drugs, so the situation where an inhibitor would be useful requires further investigation (75). …”

Section: Introductionmentioning

confidence: 99%

Autophagy, Metabolism, and Cancer

White

Mehnert

Chan

2015

Clinical Cancer Research

554

445

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Macroautophagy (autophagy hereafter) captures intracellular proteins and organelles and degrades them in lysosomes. The degradation breakdown products are released from lysosomes and recycled into metabolic and biosynthetic pathways. Basal autophagy provides protein and organelle quality control by eliminating damaged cellular components. Starvation-induced autophagy recycles intracellular components into metabolic pathways to sustain mitochondrial metabolic function and energy homeostasis. Recycling by autophagy is essential for yeast and mammals to survive starvation through intracellular nutrient scavenging. Autophagy suppresses degenerative diseases and has a context-dependent role in cancer. In some models, cancer initiation is suppressed by autophagy. By preventing the toxic accumulation of damaged protein and organelles, particularly mitochondria, autophagy limits oxidative stress, chronic tissue damage and oncogenic signaling, which suppresses cancer initiation. This suggests a role for autophagy stimulation in cancer prevention, although the role of autophagy in the suppression of human cancer is unclear. In contrast, some cancers induce autophagy and are dependent on autophagy for survival. Much in the way that autophagy promotes survival in starvation, cancers can use autophagy-mediated recycling to maintain mitochondrial function and energy homeostasis to meet the elevated metabolic demand of growth and proliferation. Thus autophagy inhibition may be beneficial for cancer therapy. Moreover, tumors are more autophagy-dependent than normal tissues, suggesting that there is a therapeutic window. Despite these insights, there remain many important, unanswered questions about the exact mechanisms of autophagy-mediated cancer suppression and promotion, how relevant these observations are to humans, and whether the autophagy pathway can be modulated therapeutically in cancer.

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Context-dependent role of ATG4B as target for autophagy inhibition in prostate cancer therapy

Cited by 34 publications

References 33 publications

Coxsackievirus can exploit LC3 in both autophagy-dependent and -independent manners in vivo

Coxsackievirus can exploit LC3 in both autophagy-dependent and -independent manners in vivo

The functional and pathologic relevance of autophagy proteases

Autophagy, Metabolism, and Cancer

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