Tumor suppressive autophagy in intestinal stem cells controls gut homeostasis

Zhang, Peng; Holowatyj, Andreana N.; Ulrich, Cornelia M.; Edgar, Bruce A.

doi:10.1080/15548627.2019.1633863

Cited by 17 publications

(11 citation statements)

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“…Mating and SP also cause inflammation and decreased life span, and these changes were found to be reversed by feeding the mated females the drug mifepristone, ( Landis et al, 2015 ; Tower et al, 2017 ). Aging in Drosophila is reported to involve further ISC proliferation and mis-differentiation (“dysplasia”), regulated in part by oxidative stress, EGFR signaling, and the microbiome ( Zhang et al, 2019 ; Zwick et al, 2019 ; Morris and Jasper, 2021 ). Mifepristone was first used in Drosophila as an activating trigger for the Gene-Switch artificial transcription factor ( Osterwalder et al, 2001 ; Roman et al, 2001 ; Ford et al, 2007 ), however, the ability of mifepristone to reduce inflammation and increase life span in the mated female does not require the presence of Gene-Switch ( Landis et al, 2015 ; Tower et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

et al. 2021

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Background: The synthetic steroid mifepristone is reported to have anti-obesity and anti-diabetic effects in mammals on normal and high-fat diets (HFD). We previously reported that mifepristone blocks the negative effect on life span caused by mating in female Drosophila melanogaster.Methods: Here we asked if mifepristone could protect virgin females from the life span-shortening effect of HFD. Mifepristone was assayed for effects on life span in virgin females, in repeated assays, on regular media and on media supplemented with coconut oil (HFD). The excrement quantification (EX-Q) assay was used to measure food intake of the flies after 12 days mifepristone treatment. In addition, experiments were conducted to compare the effects of mifepristone in virgin and mated females, and to identify candidate mifepristone targets and mechanisms.Results: Mifepristone increased life span of virgin females on regular media, as well as on media supplemented with either 2.5 or 5% coconut oil. Food intake was not reduced in any assay, and was significantly increased by mifepristone in half of the assays. To ask if mifepristone might rescue virgin females from all life span-shortening stresses, the oxidative stressor paraquat was tested, and mifepristone produced little to no rescue. Analysis of extant metabolomics and transcriptomics data suggested similarities between effects of mifepristone in virgin and mated females, including reduced tryptophan breakdown and similarities to dietary restriction. Bioinformatics analysis identified candidate mifepristone targets, including transcription factors Paired and Extra-extra. In addition to shortening life span, mating also causes midgut hypertrophy and activation of the lipid metabolism regulatory factor SREBP. Mifepristone blocked the increase in midgut size caused by mating, but did not detectably affect midgut size in virgins. Finally, mating increased activity of a SREBP reporter in abdominal tissues, as expected, but reporter activity was not detectably reduced by mifepristone in either mated or virgin females.Conclusion: Mifepristone increases life span of virgin females on regular and HFD without reducing food intake. Metabolomics and transcriptomics analyses suggest some similar effects of mifepristone between virgin and mated females, however reduced midgut size was observed only in mated females. The results are discussed regarding possible mifepristone mechanisms and targets.

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Section: Introductionmentioning

confidence: 99%

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

et al. 2021

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“…However, under conditions of starvation or oxidative stress, autophagy can also provide nutrients and energy to established metastatic tumors. In this way, autophagy can paradoxically act as a cancer-promoting factor [20]. Tumor cells can reuse proteins and damaged organelles through autophagy, and therefore survive despite drug treatment.…”

Section: Introductionmentioning

confidence: 99%

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Liu

Liao

et al. 2020

Cancers

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The difficulty of early diagnosis and the development of drug resistance are two major barriers to the successful treatment of cancer. Autophagy plays a crucial role in several cellular functions, and its dysregulation is associated with both tumorigenesis and drug resistance. Unc-51-like kinase 1 (ULK1) is a serine/threonine kinase that participates in the initiation of autophagy. Many studies have indicated that compounds that directly or indirectly target ULK1 could be used for tumor therapy. However, reports of the therapeutic effects of these compounds have come to conflicting conclusions. In this work, we reviewed recent studies related to the effects of ULK1 on the regulation of autophagy and the development of drug resistance in cancers, with the aim of clarifying the mechanistic underpinnings of this therapeutic target.

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“…Tomato yellow leaf curlvirus has been proved to enter whitefly Bemisia tabaci midgut epithelial cells through receptor-mediated clathrin-dependent endocytosis [37]. Zhang et al [38] reported that inhibition of endocytosis induced the proliferation of Drosophila intestinal stem cells and massive gut hyperplasia, which further affected intestinal development and lifespan. In this study, endocytosis-associated genes were found to be targeted by 60 DEpiRNAs in the Am4 vs. Am5 comparison group including piR-ame-14055 and piR-ame-456655 and five DEpiRNAs in the Am5 vs. Am6 comparison group it was regulated by such as piR-ame-31653 and piR-ame-1173337, indicating that corresponding DEpiRNAs potentially regulated the endocytosis during the development of larval guts.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-wide characterization of piRNAs during the developmental process of European honey bee larval guts

Long

Fan

et al. 2022

Preprint

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piRNAs play pivotal roles in suppressing transposons, maintaining genome stability, regulating gene expression, and modulating development and immunity. However, there are few piRNA-associated studies on honey bee, and the regulatory role of piRNAs in the development of bee guts is largely unknown. In this current work, the differential expression pattern of piRNAs during the developmental process of the European honey bee (Apis mellifera) was analyzed, and target prediction of differentially expressed piRNAs (DEpiRNAs) was then conducted, followed by investigation of regulatory networks and the potential function of DEpiRNAs in regulating larval gut development. Here, a total of 843 piRNAs were identified in the larval guts of A. mellifera; among these, 764 piRNAs were shared by 4- (Am4 group), 5- (Am5 group), and 6-day-old (Am6 group) larval guts, while 11, 67, and 1, respectively, were unique. The first base of piRNAs in each group had a cytosine (C) bias. Additionally, 61 up-regulated and 17 down-regulated piRNAs were identified in the Am4 vs. Am5 comparison group, further targeting 9, 983 genes, which were in-volved in 50 GO terms and 142 pathways, while two up-regulated and five down-regulated piRNAs were detected in the Am5 vs. Am6 comparison group, further targeting 1, 936 genes, which were engaged in 41 functional terms and 101 pathways. piR-ame-742536 and piR-ame-856650 in the Am4 vs. Am5 comparison group as well as piR-ame-592661 and piR-ame-31653 in the Am5 vs. Am6 comparison group were found to link to the highest number of targets. Further analysis in-dicated that targets of DEpiRNAs in these two comparison groups were seven develop-ment-associated signaling pathways such as Hippo and Notch signaling pathways, seven im-mune-associated pathways including endocytosis and the Jak/STAT signaling pathway, and three energy metabolism pathways, namely sulfur metabolism, nitrogen metabolism, and oxidative phosphorylation. Moreover, the expression trends of five randomly selected DEpiRNAs were ver-ified based on stem-loop RT-PCR and RT-qPCR. These results were suggestive of the overall alter-ation of piRNAs during the larval developmental process and demonstrated that DEpiRNAs po-tentially modulate development-, immune-, and energy metabolism-associated pathways by regu-lating expression of corresponding genes via target binding, further affecting the development of A. mellifera larval guts. Our data offer novel insights into the development of bee guts and lay a basis for clarifying the developmental mechanism underlying the larval guts of European honey bee.

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Tumor suppressive autophagy in intestinal stem cells controls gut homeostasis

Cited by 17 publications

References 1 publication

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Transcriptome-wide characterization of piRNAs during the developmental process of European honey bee larval guts

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