Abstract
Matrix metalloproteinases (Mmps) are pivotal extracellular proteinases that have been implicated in tumour invasion and metastasis. Drosophila fat body is important for energy storage and utilization, as well as biosynthetic and metabolic activities. The fat body undergoes remodelling during metamorphosis which is characterized by the dissociation of the fat body into individual cells. Mmps play important roles in the regulation of fat body cell dissociation. Here we show that a zinc transporter fear-of-intimacy (foi) is necessary for the cell dissociation of fat body in Drosophila. The progression of fat body cell dissociation was delayed by fat body-specific foi knockdown while it was accelerated by foi overexpression (OE). In essence, these phenotypes are closely associated with intracellular zinc homeostasis, which can be modulated by dietary zinc intervention or genetic modulation of other zinc transporters. Further study indicated that Mmp1 and Mmp2 levels could be transcriptionally regulated by zinc in vivo. Consistently, the retarded fat body cell dissociation caused by Mmp1 or Mmp2 RNAi could be regulated by modulating the expression of foi. Further, by using Drosophila models of malignant tumour RafGOFscrib−/− and RasV12lgl−/−, we showed that the tumour growth, invasion and migration could be markedly inhibited by foi knockdown. These findings demonstrate a close connection between zinc levels and cell dissociation in vivo, and also suggest that manipulation of zinc levels may provide a novel therapeutic strategy for cancer.
Highlights
Mammalian matrix metalloproteinases (Mmps) participated in the degradation of various proteins in the extracellular matrix (ECM) [1]
Drosophila fat body undergoes remodelling during early stages of metamorphosis, and the fat body is gradually remodelled from a single-cell layer of attached polygonal cells into free floating as single cells or as small clusters [10]
Mmp1 cleaves cell–cell junctions mediated by DE-cadherin, while Mmp2 degrades basement membrane (BM) components maintained by integrin βPs [16]
Summary
Mammalian matrix metalloproteinases (Mmps) participated in the degradation of various proteins in the extracellular matrix (ECM) [1]. Previous work showed that Mmp and Mmp are required for fat body cell dissociation in Drosophila [16]. Further study indicated that the altered transcription of Mmps is responsible for the modulation of zinc on fat body cell dissociation. Alkaline phosphatase (ALP) activity assay Samples (fat bodies of 15 larvae) were lysed in ALP lysis buffer (10 mM TrisHCl, 0.5 mM MgCl2 and 0.1% Triton X-100, pH 7.4), 1~2 μg total protein was incubated in 1.0 M diethanolamine, 0.5 mM MgCl2 and 150 mM p-nitrophenyl phosphate (pNPP). Quantitative measurements of fat body cell dissociation The fat body was dissected out from each animal at different developmental stages under Nikon camera. For analysing fat body cell dissociation of each genotype at one developmental stage, 3–10 animals were used for each independent replication and three independent replications were carried out. Asterisks indicate critical levels of significance (*P < 0.05, **P < 0.01 and ***P < 0.001)
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