The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis

Aslan

Journal of Cell Science

et al. 2017

Vertebrate proteins that fulfill multiple and seemingly disparate functions are increasingly recognized as vital solutions to maintaining homeostasis in the face of the complex cell and tissue physiology of higher metazoans. However, the molecular adaptations that underpin this increased functionality remain elusive. In this Commentary, we review the PACS proteins -which first appeared in lower metazoans as protein traffic modulators and evolved in vertebrates to integrate cytoplasmic protein traffic and interorganellar communication with nuclear gene expression -as examples of protein adaptation 'caught in the act'. Vertebrate PACS-1 and PACS-2 increased their functional density and roles as metabolic switches by acquiring phosphorylation sites and nuclear trafficking signals within disordered regions of the proteins. These findings illustrate one mechanism by which vertebrates accommodate their complex cell physiology with a limited set of proteins. We will also highlight how pathogenic viruses exploit the PACS sorting pathways as well as recent studies on PACS genes with mutations or altered expression that result in diverse diseases. These discoveries suggest that investigation of the evolving PACS protein family provides a rich opportunity for insight into vertebrate cell and organ homeostasis.

Section: Discussionmentioning

confidence: 99%

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

Aslan

Journal of Cell Science

et al. 2017

“…Apoptosis, necrosis/necroptosis and autophagy can all occur independent of, or simultaneously with, each other. In some situations, a specific stimulus evokes only one of the processes but in other situations, a combined cell death phenotype is observed in response to the same stimulus (10). In this view, it was found that Bcl-x L /Bcl-2 plays an important role in autophagic process (11), thanks to its binding with Beclin 1, an autophagy-related protein (12,13).…”

Section: Introductionmentioning

confidence: 84%

“…Cancer, a complex genetic disease resulting from mutation of oncogenes or tumour suppressor genes, can be developed due to alteration of signalling pathways; it has been well known to have numerous links to programmed cell death (PCD). Despite the remarkable progress in the classification of the different cell death modes according to the morphological presentation, signalling pathways and type of stimuli, cell death in vivo often comprises a complex interplay between apoptosis, necrosis/necroptosis, a novel form of caspase-independent PCD, and autophagy (10). Apoptosis, necrosis/necroptosis and autophagy can all occur independent of, or simultaneously with, each other.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of Bcl-xl/Mcl-1 synthetic inhibitor JY-1-106 and retinoids for human triple-negative breast cancer treatment

et al. 2018

Abstract. Overexpression of anti-apoptotic proteins belonging to the B cell lymphoma (Bcl)-2 family is observed in numerous cancer types and has been postulated to promote cancer cell survival and chemotherapy resistance. Bcl-extra large (x L) /myeloid cell leukemia sequence (Mcl)-1 was demonstrated to be expressed at relatively high levels in clinically aggressive basal-like cancers and inhibiting Bcl-x L overexpression could potentially provoke cell death. A molecule able to target Bcl-x L /Mcl-1, JY-1-106, is herein under investigation. It is also known that vitamin A-derived compounds exhibit antitumor activity in a variety of in vitro experimental models, promoting their effects via nuclear receptor isoforms including retinoic acid receptors (RARs). Pre-clinical observation highlighted that triple negative (estrogen receptor/progesterone receptor/human epidermal growth factor receptor)-breast cancer cells displayed resistance to retinoids due to the RARγ high expression profile. The present study used the triple-negative human breast cancer cell line, MDA-MB-231, to analyze the effects of the Bcl-x L /Mcl-1 synthetic inhibitor, JY-1-106, alone or in combination with retinoids on cell viability. The results revealed a synergistic effect in reducing cell viability primarily by using JY-1-106 with the selective RARγ antagonist SR11253, which induces massive autophagy and necrosis. Furthermore, the results highlighted that JY-1-106 alone is able to positively influence the gene expression profile of p53 and RARα, providing a therapeutic advantage in human triple-negative breast cancer treatment. IntroductionThe B-cell lymphoma/leukemia-2 (Bcl-2) family proteins are central regulators of cell death having both anti-and pro-apoptotic biochemical action. In humans, six anti-apoptotic members of this family have been identified, Bcl-2, Bcl-x L , Bcl-B, Bcl-W, Bfl-1, and Mcl-1, further divided into three groups on the basis of their Bcl-2 homology, in which the BH3 domain explicate the main role in the anti-apoptotic signaling (1).Bcl-2 and the anti-apoptotic proteins Mcl-1 and Bcl-x L were found to be co-expressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers (2-5). The anti-apoptotic Bcl-2 proteins neutralize the cell-killing function of the pro-apoptotic family members engaging their BH3 domains. Therefore, small-molecule designed to target BH3 domain such as the mimetic showed therapeutic potential for treating cancer (6-8). Although, ABT-263 evidenced promising results for solid tumor such as small lung cancer cells and other non-hematological malignancies, the clinical trial was early stopped due to its severe side effect (7). Finally, only ABT-199 was recently approved (April 2016) by US-FDA as Venetoclax for the pharmacological treatment of Chronic Lymphocytic Leukemia (8). Currently, the activity of Bcl-2 family inhibitors is the subject of interest in an intense area of research concerning therapeutic agents against...

“…Recent studies uncovered the underlying mechanism of autophagy, triggered by oxidized lipids, pro-inflammation factors, and metabolic stress conditions in controlling diverse cardiovascular functions [9, 10]. Similar to the process of apoptosis, autophagy is also a multistage progression that is subjected to gene regulation under some physiologic or pathologic circumstances [11]. …”

Section: Introductionmentioning

confidence: 99%

Ox-LDL-Induced MicroRNA-155 Promotes Autophagy in Human Endothelial Cells via Repressing the Rheb/ mTOR Pathway

Lv¹,

Yang²,

Guo³

et al. 2017

Cell Physiol Biochem

Background/Aims: Autophagy, an evolutionary conserved biological process, is activated in cells to cope with various types of stress. MicroRNAs control several activities related to autophagy. However, the role of autophagy-related microRNAs during atherosclerosis is far from known. MicroRNA-155 was identified to be a crucial regulator of atherosclerosis. The objectives of the study were to analyze the effect of microRNA-155 on autophagic signaling and explore its mechanism in human endothelial cells under ox-LDL stress. Methods: The study included human endothelial cells surrogate EA.hy926 lines (EA.hy926 cells). The expression of microRNA-155 was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of microRNA-155 on endothelial autophagy was observed along with the expression levels of Rheb, LC3B, Beclin1, and P62/SQSTM1 by western blotting (WB) and immunofluorescence through microRNA-155 overexpression or inhibition. Bioinformatics analysis and Luciferase reporter assay were used to explore the target gene of microRNA-155. Cell viability and apoptosis were examined by 3-[4,5-dimethylthiazol-2-yl]-5- [3-carboxy-methoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium inner salt (MTS) assay and TdT-mediated dUTP Nick-End Labeling (TUNEL) apoptosis assay. Results: MicroRNA-155 expression was significantly increased under ox-LDL stress. MicroRNA-155 increased autophagic activity, while inhibition of it alleviated ox-LDL-induced autophagy in EA.hy926 endothelial cells. In addition, dual-luciferase reporter assays showed that microRNA-155 suppressed Rheb transcription. MicroRNA-155 increased autophagic activity in EA.hy926 cells via inhibition of Rheb-mediated mTOR/P70S6kinase/4EBP signaling pathway. Furthermore, we demonstrated that microRNA-155 could regulate not only autophagy but also apoptosis in EA.hy926 cells. Conclusions: MicroRNA-155 works as a regulator of endothelial function under ox-LDL stress, making it a potential candidate for the novel therapeutic strategies against atherosclerotic diseases.