Anti-tumour effects of antimicrobial peptides, targets of the innate immune system, against haematopoietic tumours 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 mxcmbn1 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.