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Anti-tumor effects of antimicrobial peptides, targets of the innate immune system, against hematopoietic tumors in Drosophila mxc mutants

ABSTRACT: The innate immune response is the first line of defence against microbial infections. In Drosophila, two major immune pathways induce the synthesis of antimicrobial peptides (AMPs) in the fat body. Recently, it has been reported that certain cationic AMPs exhibit selective cytotoxicity against human cancer cells. However, not much is known about their anti-tumour effects. Drosophila mxc(mbn1) mutants exhibit malignant hyperplasia in a larval haematopoietic organ called the lymph gland (LG). Here, using RNA-Seq analysis, we found that many immunoresponsive genes, including AMP genes, were up-regulated in the mutants. Down-regulation of these pathways by either a Toll or an imd mutation enhanced the tumour phenotype of the mxc mutants. Conversely, ectopic expression of each of five different AMPs in the fat body significantly suppressed the LG hyperplasia phenotype in the mutants. Thus, we propose that the Drosophila innate immune system can suppress the progression of haematopoietic tumours by inducing AMP gene expression. Overexpression of any one of these five AMPs resulted in enhanced apoptosis in the mutant LGs, while no apoptotic signals were detected in the controls. We observed that two AMPs, Drosomycin and Defensin, were taken up by circulating haemocyte-like cells, which were associated with the LG regions showing reduced cell-to-cell adhesion in the mutants. On the other hand, another AMP, Diptericin, was directly localised at the tumour site without intermediating haemocytes. These results indicate that AMPs have a specific cytotoxic effect that enhance apoptosis exclusively in the tumour cells.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE121551 | GEO | 2019/06/12

REPOSITORIES: GEO

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Project description:The intricate regulation of gut homeostasis is dependent on a fine-tuned regulation of the host defense to avoid detrimental immune activation. We have previously applied Drosophila to show that mutants of the short isoform of the POU transcription factor Pdm1/nubbin (nub) have a constitutively active immune response, altered gut microbiota and shortened lifespan. Here, we studied the role of Nub-PB, the larger isoform derived from the nub gene. Both Nub protein isoforms contain the C-terminal POU and Homeo domains whereas Nub-PB encompasses a longer N-terminal end. Microarray analysis revealed that targeted misexpression of Nub-PB in immunocompetent organs triggers a strong and broad expression of immune genes in a comparable manner to Nub-PD mutants. The seemingly antagonistic functions of the two isoforms were confirmed by co-overexpression of both forms, which resulted in normal expression levels of antimicrobial peptide (AMP) genes. Cell line experiments demonstrated a synergistic activation of AMPs by the combined transfection with Nub-PB and NF-kB/Relish. In agreement with this finding, Relish was indispensable for Nub-PB-driven diptericin expression, suggesting that Nub-PB acts as a Relish co-activator. Moreover, Nub-PB triggered strong expression of gut-specific drosomycin-like genes in a JAK/STAT pathway-dependent manner. Using RNA interference, we found that Nub-PB influences antimicrobial peptide expression in gut but not fat body tissues. Moreover, Nub-PB expression levels in gut enterocytes correlated with the gut bacterial load as well as host lifespan, suggesting a profound role in host immunity. Surprisingly, Nub-PB-overexpression caused a hypersensitive infection phenotype as flies succumbed within 24 h to orally administered Erwinia carotovora carotovora 15. Nub-PB thus appears to be a central activator of gut immunity that requires tight control, executed at least in part, by isoform antagonism to maintain immune homeostasis.

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Anti-tumor effects of antimicrobial peptides, targets of the innate immune system, against hematopoietic tumors in Drosophila mxc mutants

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