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Inflammation-modulated Metabolic Reprogramming is Required for DUOX-dependent Gut Immunity in Drosophila

ABSTRACT: DUOX, a member of the NADPH oxidase family, acts as the first line of host defense against enteric pathogen by producing microbicidal reactive oxygen species. Despite the extensive research conducted, the elucidation of the DUOX regulatory mechanism remains incomplete. Here, by taking advantages of the Drosophila genetic tools, we showed that enteric infection acts as a ‘pro-catabolic’ signaling capable of initiating metabolic reprogramming of enterocytes toward lipid catabolism through activation of complex signaling cascades involving TNF receptor-associated factor 3, AMP-activated protein kinase, Warts kinase of the Hippo pathway, and ATG1 kinase of autophagy. We further showed that inflammation-modulated metabolic reprogramming is necessary for cellular NADPH homeostasis, which is essential for sustained DUOX activity and host survival during enteric infection. The discovery of signaling cascades governing inflammation-induced metabolic reprogramming will provide a novel perspective on physiology and pathophysiology of immune-metabolic interactions in microbe-laden gut epithelia.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE99642 | GEO | 2017/09/28

SECONDARY ACCESSION(S): PRJNA389132

REPOSITORIES: GEO

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Project description:In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

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Inflammation-modulated Metabolic Reprogramming is Required for DUOX-dependent Gut Immunity in Drosophila

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