The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis

Wang, Gaoxiang; Zhou, Pan; Chen, Xing; Zhao, Lei; Tan, Jiaqi; Yang, Yang; Fang, Yong; Zhou, Jianfeng

doi:10.1080/15384047.2017.1345386

Cited by 33 publications

(25 citation statements)

References 54 publications

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“…B,C). To test whether ER stress results in cell apoptosis in the mutant liver, TUDCA, an inhibitor of ER stress , was used to treat mutants. While TUDCA application could restore ER stress level to the normal level (Fig.…”

Section: Resultsmentioning

confidence: 99%

Beclin 1 deficiency causes hepatic cell apoptosis via endoplasmic reticulum stress in zebrafish larvae

et al. 2019

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Edited by Didier StainierBeclin 1/Atg6 is an essential autophagy gene, and deficiency of this gene in organisms leads to impaired autophagic flux, usually with cell apoptosis; however, the causative mechanism of cell apoptosis is not clear. Here, we knocked out the beclin 1 gene in zebrafish and found that autophagic flux is disrupted in mutants. Beclin 1-deficient zebrafish live through embryogenesis but die at larval stage. We found accumulated protein aggregates and vigorous apoptosis in mutant larvae, predominantly in the liver. The hepatic cell apoptosis in mutants results from an endoplasmic reticulum (ER) stress response; however, it is not the leading cause of mutant larval lethality. Our work proposes that ER stress induces cell apoptosis in Beclin 1-deficient organisms.Autophagy is an ancient self-digestive mechanism in eukaryotic cells, delivering cytoplasmic materials into the lysosome for degradation. The cargoes include damaged organelles, aberrant proteins, invading pathogens, and other cellular contents. The digestive products can be used for macromolecule synthesis and energy production. Therefore, autophagy plays important roles in the maintenance of cellular hemostasis, response to energy deprivation, and clearance of invading microorganism pathogen [1,2]. Among the three types of autophagy, namely microautophagy, chaperone-mediated autophagy, and macroautophagy, macroautophagy draws the most attention [3,4] and is hereafter called autophagy in this study. Autophagy is regulated by a group of genes, known as autophagy-related gene (Atg), with majority of them firstly identified by genetic screens in yeast and highly conserved among species [5]. Beclin 1/Atg6 is an essential for autophagy induction. It directly binds to Vps34 (Pik3c3) through its evolutionarily conserved domain (ECD) forming the class III phosphatidylinositol 3-kinase (PI3KIII) complex to produce phosphatidylinositol 3-phosphate (PtdIns(3)P), an essential lipid-based compound for initial steps of autophagosome formation [6].To study the biological functions of Beclin 1/Atg6, the loss-of-function mutants were generated in many Abbreviations Atg, autophagy-related gene; BH3, Bcl-2 homology-3 domain; CCD, coiled-coil domain; ECD, evolutionarily conserved domain; ER, endoplasmic reticulum; PC, Purkinje cell; PI3KIII, class III phosphatidylinositol 3-kinase; PtdIns(3)P, phosphatidylinositol 3-phosphate; TUDCA, tauroursodeoxycholic acid; VE, visceral endoderm; WISH, Whole-mount in situ hybridization.

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Section: Resultsmentioning

confidence: 99%

Beclin 1 deficiency causes hepatic cell apoptosis via endoplasmic reticulum stress in zebrafish larvae

et al. 2019

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“…Inhibition of autophagy by Beclin-1 knockdown or treatment with autophagy inhibitors, i.e., 3-methyladenine (3-MA) and chloroquine, induces MM cells apoptosis [88] , [89] and blocks autophagosome formation. Recently, Wang et al [90] demonstrated that elaiophylin, a potent inhibitor of late stage of autophagy, has an anti–MM cell activity via inhibition of the autophagic flux and persistent activation of ER stress–mediated apoptosis. On the other hand, basal autophagy is tightly regulated to avoid autophagic cell death.…”

Section: Autophagy As Prosurvival Machinery In MMmentioning

confidence: 99%

Autophagy: A New Mechanism of Prosurvival and Drug Resistance in Multiple Myeloma

Desantis

Saltarella

Lamanuzzi

et al. 2018

Translational Oncology

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Autophagy is an intracellular self-degradative process that balances cell energy source and regulates tissue homeostasis. In physiological condition, autophagy funnels cytoplasmic constituents to autophagolysosomes for degradation and is an alternative way for cell-death behavior. Here, we inspected autophagy as a prosurvival mechanism essential for drug resistance in multiple myeloma (MM). Accordingly, autophagy inhibitors used in association to conventional anti-MM drugs might enforce the effect against resistant MM plasma cells and render autophagy a new therapeutic target.

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“…Clarithromycin suppresses autophagy by inhibiting the interaction between the hERG1 potassium channel and PI3K in colorectal cancer ( Altman and Platanias, 2012 ; Petroni et al ., 2020 ). Elaiophylin, a macrolide antibiotic with immunosuppressive properties, inhibits the autophagic flux and has anti-tumor activity in ovarian cancer ( Zhao et al ., 2015 ) and multiple myeloma with mutant TP53 ( Wang et al ., 2017 ).…”

Section: Autophagy Inhibitors In Cancer Therapymentioning

confidence: 99%

Dual Roles of Autophagy and Their Potential Drugs for Improving Cancer Therapeutics

Shin

2020

Biomolecules & Therapeutics

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Autophagy is a major catabolic process that maintains cell metabolism by degrading damaged organelles and other dysfunctional proteins via the lysosome. Abnormal regulation of this process has been known to be involved in the progression of pathophysiological diseases, such as cancer and neurodegenerative disorders. Although the mechanisms for the regulation of autophagic pathways are relatively well known, the precise regulation of this pathway in the treatment of cancer remains largely unknown. It is still complicated whether the regulation of autophagy is beneficial in improving cancer. Many studies have demonstrated that autophagy plays a dual role in cancer by suppressing the growth of tumors or the progression of cancer development, which seems to be dependent on unknown characteristics of various cancer types. This review summarizes the key targets involved in autophagy and malignant transformation. In addition, the opposing tumor-suppressive and oncogenic roles of autophagy in cancer, as well as potential clinical therapeutics utilizing either regulators of autophagy or combinatorial therapeutics with anti-cancer drugs have been discussed.

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The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis

Cited by 33 publications

References 54 publications

Beclin 1 deficiency causes hepatic cell apoptosis via endoplasmic reticulum stress in zebrafish larvae

Beclin 1 deficiency causes hepatic cell apoptosis via endoplasmic reticulum stress in zebrafish larvae

Autophagy: A New Mechanism of Prosurvival and Drug Resistance in Multiple Myeloma

Dual Roles of Autophagy and Their Potential Drugs for Improving Cancer Therapeutics

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