Identification of breast cancer cell subtypes sensitive to ATG4B inhibition

Bortnik, Svetlana; Choutka, Courtney; Horlings, Hugo M.; Leung, Samuel; Baker, Jennifer H.E.; Lebovitz, Chandra B.; Dragowska, Wieslawa H.; Go, Nancy E.; Bally, Marcel B.; Minchinton, Andrew I.; Gelmon, Karen A.; Gorski, Sharon M.

doi:10.18632/oncotarget.11408

Cited by 58 publications

(59 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These patients were diagnosed with invasive breast cancer at the University of British Columbia hospitals between 1989 and 2002 and have been previously described 44 . A detailed description of the validation set consisting of 3,992 breast cancer patients has been previously published 45,46 .…”

Section: Methodsmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

Self Cite

View full text Add to dashboard Cite

Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

show abstract

Section: Methodsmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The resulting ATG12-ATG5 heterodimer then binds ATG16L1, altogether completing the core of the ATG16L1 complex [9], [50], [55]. LC3 is cleaved by the cysteine protease ATG4B, yielding LC3-I, which is subsequently transferred by ATG7 to the inner and outer membrane of the expanding phagophore [57]- [59]. There, LC3-I is passed over to ATG3 and by the localized operations of the PI3K-III and ATG16L1 complexes it is lipidated to LC3-II and anchored to the autophagosomal membrane [57]- [59].…”

Section: Phagophore Nucleation and Expansionmentioning

confidence: 99%

“…During fusion of the mature autophagosome with a lysosome, the ATG16L1-complex dissociates from the vesicle and ATG4B removes the cytosolic fraction of LC3-II [43], [57], [59].…”

Section: Maturation and Fusion With Lysosomesmentioning

confidence: 99%

“…Elongation; Maturation Atg4B most active in mammals; Cysteine protease priming LC3 for lipidation by cleaving carboxy-terminal Gly residues; removes LC3 from the autophagosome outer membrane during maturation [56], [57], [59] ATG7 Elongation E1-like enzyme; activates ATG12 for conjugation to Atg16L1 complex; Primes LC3 for lipidation [16], [43] LC3/ GABARAP/ GATE16,…”

Section: Proteinmentioning

confidence: 99%

See 1 more Smart Citation

Caspase involvement in autophagy

2017

View full text Add to dashboard Cite

Caspases are a family of cysteine proteases widely known as the principal mediators of the apoptotic cell death response, but considerably less so as the contributors to the regulation of pathways outside cellular demise. In regards to autophagy, the modulatory roles of caspases have only recently begun to be adequately described. In contrast to apoptosis, autophagy promotes cell survival by providing energy and nutrients through the lysosomal degradation of cytoplasmic constituents. Under basal conditions autophagy and apoptosis cross-regulate each other through an elaborate network of interconnections which also includes the interplay between autophagyrelated proteins (ATGs) and caspases. In this review we focus on the effects of this crosstalk at the cellular level, as we aim to concentrate the main observations from research conducted so far on the fine-tuning of autophagy by caspases. Several members of this protease-family have been found to directly interact with key ATGs involved in different tiers across the autophagic cascade. Therefore, we firstly outline the core mechanism of macroautophagy in brief. In an effort to emphasize the importance of the intricate cross-regulation of ATGs and caspases, we also present examples drawn from Drosophila and plant models regarding the contribution of autophagy to apoptotic cell death during normal development. Keywords and abbreviationsautophagy; macroautophagy; mammals; caspases; apoptosis; crosstalk; regulation AMBRA-1Activating-molecule-in-Beclin1-regulated-autophagy-1 AMPK AMP-activated-protein-kinase ATG Autophagy-related gene ATG14L ATG14-likeBcl-2 B-cell lymphoma 2 • Autophagy is implicated in many physiological and pathological processes, where apoptosis is also involved DISC Death-inducing signalling complex FADD Fas-associated protein with death domain Open Questions• Does control of autophagy by caspases represent a central or a supplementary mode of regulation of this pathway?• Is caspase activation required to control autophagy?• To what extent do caspases affect autophagy and how exactly their effects on the pathway vary across different contexts?4

show abstract

“…The association of ATG4B with cancer has been recently reported [9-11]. In colorectal cancer patients, ATG4B is highly expressed in tumor cells, whereas it is minimally expressed in adjacent normal cells [10].…”

Section: Introductionmentioning

confidence: 99%

Ablation of ATG4B Suppressed Autophagy and Activated AMPK for Cell Cycle Arrest in Cancer Cells

Liu

Hsu

Tsai

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: ATG4B is a cysteine protease required for autophagy, which is a cellular catabolic pathway involved in energy balance. ATG4B expression is elevated during tumor growth in certain types of cancer, suggesting that ATG4B is an attractive target for cancer therapy. However, little is known about the mechanisms through which ATG4B deprivation suppresses the growth of cancer cells. Methods: Cancer cells were transfected with either siRNA against ATG4B or an expression vector encoding wild-type ATG4B^WT or encoding catalytic mutant ATG4B^C74A to determine cell cycle progression by propidium iodide staining or by BrdU incorporation assay using flow cytometry. The GFP-MAP1LC3-II puncta and protein levels in the cells were determined by immunofluorescence and immunoblotting, respectively. Results: Knockdown of ATG4B blocked cell proliferation, particularly at the G₁-S phase transition, in various cancer cells. Moreover, knockdown of ATG4B or overexpression of the ATG4B^C74A catalytic mutant reduced both autophagic flux and ATP levels and increased AMP-activated protein kinase (AMPK) phosphorylation in the cancer cells. Nevertheless, knockdown of ATG4B had only a minor effect on AMPK activation and G₁ phase arrest in liver kinase B1 (LKB1)-deficient or AMPK-inhibited cancer cells. Conclusion: These results imply that targeting ATG4B might inhibit autophagy and trigger the LKB1-AMPK energy-sensing pathway, resulting in tumor growth suppression.

show abstract

Identification of breast cancer cell subtypes sensitive to ATG4B inhibition

Cited by 58 publications

References 65 publications

TIM-3 expression in breast cancer

TIM-3 expression in breast cancer

Caspase involvement in autophagy

Ablation of ATG4B Suppressed Autophagy and Activated AMPK for Cell Cycle Arrest in Cancer Cells

Contact Info

Product

Resources

About