The regulatory activity of autophagy in conjunctival fibroblasts and its possible role in vernal keratoconjunctivitis

Brun, Paola; Tarricone, Elena; Stefano, Antonino Di; Mattiuzzo, Elena; Mehrbod, Parvaneh; Ghavami, Saeid; Leonardi, Andrea

doi:10.1016/j.jaci.2020.03.013

Cited by 31 publications

(21 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…UPR is connected to apoptotic cell death via different intermediates, including C/EBP homologous protein (CHOP), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA), c-Jun N-terminal kinase (JNK), and caspase-4 and caspase-12 [ 36 , 49 , 50 ]. Autophagy is also responsible for the degradation and removal of damaged organelles and misfolded proteins [ 51 , 52 , 53 ]. The term autophagic flux refers to the degradation activity of the autophagy pathway through the formation of the phagophore and engulfment of its p62-tagged cargo inside to form autophagosomes [ 41 , 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Dastghaib

Shojaei

Mostafavi‐Pour

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in GBM cells. Considering the role of the unfolded protein response (UPR) pathway in the regulation of autophagy, we investigated the involvement of UPR in Simva–TMZ-induced cell death by utilizing highly selective IRE1 RNase activity inhibitor MKC8866, PERK inhibitor GSK-2606414 (PERKi), and eIF2α inhibitor salubrinal. Simva–TMZ treatment decreased the viability of GBM cells and significantly increased apoptotic cell death when compared to TMZ or Simva alone. Simva–TMZ induced both UPR, as determined by an increase in GRP78, XBP splicing, eukaryote initiation factor 2α (eIF2α) phosphorylation, and inhibited autophagic flux (accumulation of LC3β-II and inhibition of p62 degradation). IRE1 RNase inhibition did not affect Simva–TMZ-induced cell death, but it significantly induced p62 degradation and increased the microtubule-associated proteins light chain 3 (LC3)β-II/LC3β-I ratio in U87 cells, while salubrinal did not affect the Simva–TMZ induced cytotoxicity of GBM cells. In contrast, protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibition significantly increased Simva–TMZ-induced cell death in U87 cells. Interestingly, whereas PERK inhibition induced p62 accumulation in both GBM cell lines, it differentially affected the LC3β-II/LC3β-I ratio in U87 (decrease) and U251 (increase) cells. Simvastatin sensitizes GBM cells to TMZ-induced cell death via a mechanism that involves autophagy and UPR pathways. More specifically, our results imply that the IRE1 and PERK signaling arms of the UPR regulate Simva–TMZ-mediated autophagy flux inhibition in U251 and U87 GBM cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Dastghaib

Shojaei

Mostafavi‐Pour

et al. 2020

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…The CMA acts with the membrane protein associated with type 2a lysosome (LAMP2A) and directly brings the cargo to the lysosomal membrane [ 217 , 218 ]. The main form of autophagic degradation, that of macro-autophagy, occurs through multi-level phenomena beginning with the engulfment of cytosolic components in a crescent-shaped double membrane structure called the phagophore [ 219 , 220 ].…”

Section: Definition Of the Autophagy Mechanismmentioning

confidence: 99%

The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions

Vallée

Lecarpentier²,

Vallée

2021

Cancers

View full text Add to dashboard Cite

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.

show abstract

“…Autophagy could be induced by many external and internal stimulators (e.g., chemotherapy, oxidative stress, starvation, etc.) to maintain cellular homeostasis (Brun et al 2020;Katayama et al 2007;Klionsky and Emr 2000). Nevertheless, over-activation of autophagy may lead to a specific kind of cell death, called programmed cell death type II or autophagy cell death (Maiuri et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Casein Kinase-1-Alpha Inhibitor (D4476) Sensitizes Microsatellite Instable Colorectal Cancer Cells to 5-Fluorouracil via Authophagy Flux Inhibition

Siri

Behrouj

Dastghaib

et al. 2021

Arch. Immunol. Ther. Exp.

Self Cite

View full text Add to dashboard Cite

Adjuvant chemotherapy with 5-fluorouracil (5-FU) does not improve survival of patients suffering from a form of colorectal cancer (CRC) characterized by high level of microsatellite instability (MSI-H). Given the importance of autophagy and multi-drug-resistant (MDR) proteins in chemotherapy resistance, as well as the role of casein kinase 1-alpha (CK1α) in the regulation of autophagy, we tested the combined effect of 5-FU and CK1α inhibitor (D4476) on HCT116 cells as a model of MSI-H colorectal cancer. To achieve this goal, the gene expression of Beclin1 and MDR genes, ABCG2 and ABCC3 were analyzed using quantitative real-time polymerase chain reaction. We used immunoblotting to measure autophagy flux (LC3, p62) and flow cytometry to detect apoptosis. Our findings showed that combination treatment with 5-FU and D4476 inhibited autophagy flux. Moreover, 5-FU and D4476 combination therapy induced G2, S and G1 phase arrests and it depleted mRNA of both cell proliferation-related genes and MDR-related genes (ABCG2, cyclin D1 and c-myc). Hence, our data indicates that targeting of CK1α may increase the sensitivity of HCT116 cells to 5-FU. To our knowledge, this is the first description of sensitization of CRC cells to 5-FU chemotherapy by CK1α inhibitor. Graphic abstract

show abstract

The regulatory activity of autophagy in conjunctival fibroblasts and its possible role in vernal keratoconjunctivitis

Cited by 31 publications

References 12 publications

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

Simvastatin Induces Unfolded Protein Response and Enhances Temozolomide-Induced Cell Death in Glioblastoma Cells

The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions

Casein Kinase-1-Alpha Inhibitor (D4476) Sensitizes Microsatellite Instable Colorectal Cancer Cells to 5-Fluorouracil via Authophagy Flux Inhibition

Contact Info

Product

Resources

About