Targeting Autophagy in Cancer: Recent Advances and Future Directions

Amaravadi, Ravi K.; Kimmelman, Alec C.; Debnath, Jayanta

doi:10.1158/2159-8290.cd-19-0292

Cited by 631 publications

(614 citation statements)

References 160 publications

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“…Increased levels of basal autophagy in some cancers represents a vulnerability to autophagy inhibition 5 . BRAF V600E -driven lung adenocarcinomas require autophagy to preserve mitochondrial function and supply metabolic substrates to support tumor growth 47 .…”

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confidence: 99%

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Tsang

Posimo

Gudiel

et al. 2019

Preprint

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Targeting aberrant kinase activity in cancer relies on unmasking cellular inputs such as growth factors, nutrients, and metabolites that contribute to cancer initiation and progression 1 . While the transition metal copper (Cu) is an essential nutrient that is traditionally viewed as a static cofactor within enzyme active sites 2 , a newfound role for Cu as a modulator of kinase signaling is emerging 3,4 . We discovered that Cu is required for the activity of the autophagic kinases ULK1/2 through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt Cu-binding reduced ULK1/2-dependent signaling and autophagosome complex formation. Elevated intracellular Cu levels are associated with starvation induced autophagy and sufficient to enhance ULK1 kinase activity and in turn autophagic flux. Targeting autophagy machinery is a promising therapeutic strategy in cancers 5 , but is limited by the absence of potent inhibitors and the emergence of resistance. The growth and survival of lung tumors driven by KRAS G12D is diminished in the absence of Ctr1, depends on ULK1 Cu-binding, and is associated with reduced autophagy levels and signaling. These findings suggest a new molecular basis for exploiting Cu-chelation therapy to forestall autophagy signaling to limit proliferation and survival in cancer.By default, the dynamic and adaptive nature of signaling networks allows them to respond and, in some cases, sense extracellular and intracellular inputs 6 . While growth factors, nutrients, and metabolites are well-appreciated regulators of cell proliferation, the contribution of transition metals to cellular processes that support proliferation and contribute to malignant transformation are understudied. The transition metal copper (Cu) is essential for a diverse array of biological processes from cellular proliferation, neuropeptide processing, free radical detoxification, and

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mentioning

confidence: 99%

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Tsang

Posimo

Gudiel

et al. 2019

Preprint

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“…Third, we evaluated the autophagic activity using a limited number of autophagic markers. Autophagy is a complex multistep process where more than 30 autophagy-related genes have been identified to make up the core machinery [16][17][18][19]. Although BECN1, MAP1LC3, and SQSTM1 have been used widely as immunohistochemistry-based autophagy markers in human FFPE tissues [54][55][56][57][58][59][60][61], a simultaneous multimarker evaluation of other components of the autophagic pathway might further enlighten the interactions between autophagy and microbiota.…”

Section: Discussionmentioning

confidence: 99%

Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer

Haruki

Kosumi

Hamada

et al. 2020

The Journal of Pathology

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Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti‐tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal and colon cancer cases within the Nurses' Health Study and the Health Professionals Follow‐up Study, we evaluated autophagic activity of tumour cells by immunohistochemical analyses of BECN1 (beclin 1), MAP1LC3 (LC3), and SQSTM1 (p62) expression. We measured the amount of F. nucleatum DNA in tumour tissue by quantitative polymerase chain reaction (PCR). We conducted multivariable ordinal logistic regression analyses to examine the association of tumour BECN1, MAP1LC3, and SQSTM1 expression with the amount of F. nucleatum, adjusting for potential confounders, including microsatellite instability status; CpG island methylator phenotype; long‐interspersed nucleotide element‐1 methylation; and KRAS, BRAF, and PIK3CA mutations. Compared with BECN1‐low cases, BECN1‐intermediate and BECN1‐high cases were associated with lower amounts of F. nucleatum with odds ratios (for a unit increase in three ordinal categories of the amount of F. nucleatum) of 0.54 (95% confidence interval, 0.29–0.99) and 0.31 (95% confidence interval, 0.16–0.60), respectively (Ptrend < 0.001 across ordinal BECN1 categories). Tumour MAP1LC3 and SQSTM1 levels were not significantly associated with the amount of F. nucleatum (Ptrend > 0.06). Tumour BECN1, MAP1LC3, and SQSTM1 levels were not significantly associated with patient survival (Ptrend > 0.10). In conclusion, tumour BECN1 expression is inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting a possible role of autophagy in the elimination of invasive microorganisms. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…We report the first structural view of a complex between CI-MPR and a lysosomal enzyme, PPT1, providing insight for future studies into developing therapy for newborns with infantile neuronal ceroid lipofuscinosis who are deficient in this enzyme. Recent studies showing PPT1-dependent depalmitoylation stabilizes the lysosomal localization of v-ATPase subunits, which directly impacts lysosomal acidification required for autophagylysosomal function and mTOR signaling, further emphasizes the need for proper MPR-mediated delivery of PPT1 to the lysosome 53 .…”

Section: Discussionmentioning

confidence: 99%

Allosteric regulation of lysosomal enzyme recognition by the cation-independent mannose 6-phosphate receptor

Olson

Misra

Ishihara

et al. 2020

Preprint

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The cation-independent mannose 6-phosphate receptor (CI-MPR), also known as the IGF2 receptor or CD222, is a multifunctional type I transmembrane glycoprotein ubiquitously expressed in most eukaryotic cell types. Through the receptor's ability to bind a variety of unrelated extracellular and intracellular ligands, it is involved in a wide array of functions including protein trafficking, lysosomal biogenesis, internalization, regulation of cell growth, cell migration and apoptosis. CI-MPR has a large extracellular region comprised of 15 contiguous domains, four of which interact with phosphorylated glycans on lysosomal enzymes. Here we present a series of biophysical studies, along with crystal structures, providing information on how the N-terminal 5 domains of this receptor work in concert to bind and release carbohydrates. High-resolution electron microscopy as well as hydroxyl radical protein footprinting (HRPF) of this multifunctional multidomain construct demonstrates dynamic conformational changes occur as a consequence of ligand binding and different pH conditions, These data, coupled with surface plasmon resonance studies and molecular modeling, allow us to propose a bi-dentate oligosaccharide binding model, which could explain how high affinity carbohydrate binding is achieved through allosteric domain cooperativity. Introduction:Lysosomes are acidified organelles that carry out degradative metabolism critical to many endocytic, phagocytic, and autophagic processes, such as inactivation of pathogenic organisms and disposal of abnormal proteins 1-5 . This diverse degradative capacity depends on a collection of over 60 different soluble proteases, glycosidases, nucleases, and lipases. Delivery of these newly synthesized hydrolytic enzymes to lysosomes depends on the P-type lectins, the 300kDa cation-independent mannose 6-phosphate receptor (CI-MPR) and the 46kDa cation-dependent MPR (CD-MPR), that bind a unique carbohydrate determinant, mannose 6-phosphate (M6P), on lysosomal enzymes. However, CI-MPR is the primary receptor responsible for this trafficking 4 . Because CI-MPR binds a wide range of ligands 6,7 at the cell surface that include M6P-containing cytokines/hormones 8,9 and non-M6P-containing molecules (e.g., insulin-like growth factor 2 (IGF2) 10 , plasminogen 11 , urokinase-type plasminogen activator receptor (uPAR) 11 ) to mediate CI-MPR's roles as a tumor suppressor 12 and regulator of cell growth and differentiation 13 , it is not surprising CI-MPR is essentiel for normal development as transgenic mice lacking the CI-MPR gene die at birth 14,15 .Lysosomal storage diseases (LSDs) are caused by mutations in lysosomal proteins, mainly enzymes, that result in defective catabolism and substrate accumulation. Characteristic of the family of ~70 LSDs is their progressive and debilitating nature due to their impact on multiple organ systems. Treatment is symptomatic for most LSDs, with only 11 having FDAapproved therapies. For example, deficiency of palmitoyl-protein thioesterase 1 (PPT1), which remo...

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Targeting Autophagy in Cancer: Recent Advances and Future Directions

Cited by 631 publications

References 160 publications

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer

Allosteric regulation of lysosomal enzyme recognition by the cation-independent mannose 6-phosphate receptor

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