Targeting the lysosome in cancer

Piao, Shengfu; Amaravadi, Ravi K.

doi:10.1111/nyas.12953

Cited by 237 publications

(228 citation statements)

References 79 publications

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“…Second, deletion of autophagy genes in the setting of certain mouse models can result in the initiation of neoplasia. The initial identification of this phenotype was in Beclin1 (ATG6 ortholog) heterozygous mice, whereby these mice developed various neoplasms (Qu et al, 2003; Yue et al, 2003). An important aspect to note is that in this case autophagy was only partly attenuated as a functional copy of Beclin1 was intact in the mice.…”

Section: Autophagy and Cancermentioning

confidence: 99%

Autophagy and Tumor Metabolism

2017

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Autophagy is a critical cellular process that generally protects cells and organisms from stressors such as nutrient deprivation. In addition to its role in normal physiology, autophagy plays a role in pathological processes such as cancer. Indeed, there has been substantial work exploring the complex and context-dependent role of autophagy in cancer. One of the emerging themes is that in certain cancer types, autophagy is important to support tumor growth and therefore inhibiting autophagy as a therapeutic approach is actively being tested in clinical trials. A key mechanism of how autophagy promotes the growth and survival of various cancers is its ability to support cellular metabolism. The diverse metabolic fuel sources that can be produced by autophagy provides tumors with metabolic plasticity and can allow them to thrive in what can be an austere microenvironment. Therefore, understanding how autophagy can fuel cellular metabolism will enable more effective combinatorial therapeutic strategies.

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Section: Autophagy and Cancermentioning

confidence: 99%

Autophagy and Tumor Metabolism

2017

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“…As CQ and HCQ have been used in patients for many years for a variety of indications, testing this as a therapeutic approach in cancer patients is feasible and currently ongoing[2,183]. As these agents act on the lysosome by inhibiting lysosomal acidification they inhibit the late stages of autophagy at the level of autophagosome maturation and cargo degradation[183].…”

Section: Pro-tumorigenic Functions Of Autophagymentioning

confidence: 99%

“…As these agents act on the lysosome by inhibiting lysosomal acidification they inhibit the late stages of autophagy at the level of autophagosome maturation and cargo degradation[183]. In addition, these drugs may have other non-autophagy specific therapeutic effects as they block other processes that depend on lysosomal activity.…”

Section: Pro-tumorigenic Functions Of Autophagymentioning

confidence: 99%

Mechanisms of Selective Autophagy in Normal Physiology and Cancer

Mancias

Kimmelman

2016

Journal of Molecular Biology

156

123

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Selective autophagy is critical for regulating cellular homeostasis by mediating lysosomal turnover of a wide variety of substrates including proteins, aggregates, organelles, and pathogens via a growing class of molecules termed selective autophagy receptors. The molecular mechanisms of selective autophagy receptor action and regulation are complex. Selective autophagy receptors link their bound cargo to the autophagosomal membrane by interacting with lipidated ATG8 proteins (LC3/GABARAP) that are intimately associated with the autophagosome membrane. The cargo signals that selective autophagy receptors recognize are diverse but their recognition can be broadly grouped into two classes, ubiquitin-dependent cargo recognition versus ubiquitin-independent. The roles of post-translational modification of selective autophagy receptors in regulating these pathways in response to stimuli are an active area of research. Here we will review recent advances in the identification of selective autophagy receptors and their regulatory mechanisms. Given its importance in maintaining cellular homeostasis, disruption of autophagy can lead to disease including neurodegeneration and cancer. The role of autophagy in cancer is complex as autophagy can mediate promotion or inhibition of tumorigenesis. Here we will also review the importance of autophagy in cancer with a specific focus on the role of selective autophagy receptors.

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“…The Na + /H + exchanger has also been associated with extracellular acidification and cancer cell invasion [36]. Another intriguing aspect of lysosomes is their ability to secrete contents out of the cell by fusing with the plasma membrane [4, 37]. For example, cells can expel ATP to the extracellular space with this secretory pathway to mediate cellular signaling through ATP receptors [38, 39].…”

Section: Lysosomes and Cancer Progressionmentioning

confidence: 99%

“…Bafilomycin A1 has also been shown to prevent autophagosome formation by activation of mTOR signaling, suggesting that it may target both the early and late stages of autophagy [89]. This impairment is mediated by dissociation of the Beclin1-Vps34 complex and encourages Bcl-2 interaction to drive autophagy inhibition and apoptotic cell death [37]. Interestingly, Bafilomycin has also been shown to engage the mitochondria and induce translocation of apoptosis inducing factor to the nucleus and provoke caspase-independent apoptosis [90].…”

Section: Drugs That Target the Lysosomementioning

confidence: 99%

Lysosomal Biology in Cancer

Fennelly

Amaravadi

2017

Methods in Molecular Biology

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Cells depend on the lysosome for sequestration and degradation of macromolecules in order to maintain metabolic homeostasis. These membrane-enclosed organelles can receive intracellular and extracellular cargo through endocytosis, phagocytosis, and autophagy. Lysosomes establish acidic environments to activate enzymes that are able to break down biomolecules engulfed through these various pathways. Recent advances in methods to study the lysosome have allowed the discovery of extended roles for the lysosome in various diseases, including cancer, making it an attractive and targetable node for therapeutic intervention. This review focuses on key aspects of lysosomal biology in the context of cancer and how these properties can be exploited for the development of new therapeutic strategies. This will provide a contextual framework for how advances in methodology could be applied in future translational research.

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Targeting the lysosome in cancer

Cited by 237 publications

References 79 publications

Autophagy and Tumor Metabolism

Autophagy and Tumor Metabolism

Mechanisms of Selective Autophagy in Normal Physiology and Cancer

Lysosomal Biology in Cancer

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