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Kunitz type protease inhibitor EgKI-1 from the canine tapeworm Echinococcus granulosus as a promising therapeutic against breast cancer.

ABSTRACT: EgKI-1, a member of the Kunitz type protease inhibitor family, is highly expressed by the oncosphere of the canine tapeworm Echinococcus granulosus, the stage that is infectious to humans and ungulates, giving rise to a hydatid cyst localized to the liver and other organs. Larval protoscoleces, which develop within the hydatid cyst, have been shown to possess anti-cancer properties, although the precise molecules involved have not been identified. We show that recombinant EgKI-1 inhibits the growth and migration of a range of human cancers including breast, melanoma and cervical cancer cell lines in a dose-dependent manner in vitro without affecting normal cell growth. Furthermore, EgKI-1 treatment arrested the cancer cell growth by disrupting the cell cycle and induced apoptosis of cancer cells in vitro. An in vivo model of triple negative breast cancer (MDA-MB-231) in BALB/c nude mice showed significant tumor growth reduction in EgKI-1-treated mice compared with controls. These findings indicate that EgKI-1 shows promise for future development as an anti-cancer therapeutic.

SUBMITTER: Ranasinghe SL

PROVIDER: S-EPMC6118354 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Kunitz type protease inhibitor EgKI-1 from the canine tapeworm Echinococcus granulosus as a promising therapeutic against breast cancer.

Ranasinghe Shiwanthi L SL Boyle Glen M GM Fischer Katja K Potriquet Jeremy J Mulvenna Jason P JP McManus Donald P DP

PloS one 20180831 8

EgKI-1, a member of the Kunitz type protease inhibitor family, is highly expressed by the oncosphere of the canine tapeworm Echinococcus granulosus, the stage that is infectious to humans and ungulates, giving rise to a hydatid cyst localized to the liver and other organs. Larval protoscoleces, which develop within the hydatid cyst, have been shown to possess anti-cancer properties, although the precise molecules involved have not been identified. We show that recombinant EgKI-1 inhibits the gro ...[more]

PMID: 30169534

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Project description:BackgroundCystic echinococcosis (hydatid disease), caused by the tapeworm Echinococcus granulosus (class Cestoda; family Taeniidae), is a neglected tropical disease that results in morbidity and mortality in millions of humans, as well as in huge economic losses in the livestock industry globally. Proteins from the tetraspanin family in parasites have recently become regarded as crucial molecules in interaction with hosts in parasitism and are therefore suitable for the development of vaccines and diagnostic agents. However, no information is available to date on E. granulosus tetraspanin.MethodsIn this study, a uroplakin-I-like tetraspanin (Eg-TSP1) of E. granulosus was cloned and expressed in E. coli. The immunolocalization of Eg-TSP1 in different life stages of E. granulosus was determined using specific polyclonal antibody. The antibody and cytokine profiles of mice that immunized with recombinant Eg-TSP1 (rEg-TSP1) were measured for the immunogenicity analysis of this protein. Additionally, we use RNA interference method to explore the biological function of Eg-TSP1 in larva of E. granulosus.ResultsImmunofluorescence analysis showed that endogenous Eg-TSP1 mainly localized in the tegument of larvae and adults. Significantly elevated levels of antibodies IgG1 and IgG2a and of cytokines IFN-γ and IL-12 were observed in the sera of mice after immunization with rEg-TSP1, suggesting a typical T helper (Th)1-mediated immune response elicited by rEg-TSP1. On further probing the role of Eg-TSP1 in E. granulosus by RNA interference, we found that a thinner tegmental distal cytoplasm was induced in protoscoleces treated with siRNA-132 compared to controls.ConclusionsThis is the first report characterizing a tetraspanin from the tapeworm E. granulosus. Our results suggest that Eg-TSP1 is associated with biogenesis of the tegument and maintenance of structural integrity of E. granulosus and could therefore be a candidate intervention target for control of hydatid disease.

Project description:BackgroundCystic and alveolar echinococcosis caused by the tapeworms Echinococcus granulosus sensu stricto (s.s.) and E. multilocularis, respectively, are important zoonotic diseases. Protease inhibitors are crucial for the survival of both Echinococcus spp. Kunitz-type inhibitors play a regulatory role in the control of protease activity. In this study,we identified Kunitz-type domain protease inhibitors(KDPIs) present in the genomes of these two tapeworms and analyzed the gene sequences using computational, structural bioinformatics and phylogenetic approaches to evaluate the evolutionary relationships of these genes. Hi-seq transcriptome analysis showed that E. granulosus s.s. KDPIs were differentially expressed in the different developmental stages. We validated some of the genes expressed in adult worm, protoscolex and cyst germinal membrane of E. granulosus s.s. and E. multilocularis by quantitative PCR.ResultsA total of 19 genes from E. multilocularis and 23 genes from E. granulosus s.s. were predicted to be KDPIs with the most containing a single Kunitz-domain. A maximum likelihood method phylogenetic tree indicated that the E. granulosus s.s. and E. multilocularis Kunitz domain peptides were divided into three branches containing 9 clusters. The ratio of positively charged residues and neutral residues are different between E. multilocularis and E. granulosus s.s. KDPIs. We also found that E. multilocularis had higher percentage of sequences containing signal peptides (17/19, 89.47%) than that of E. granulosus s.s. (14/23, 60.87%). Transcript analysis showed all the E. granulosus s.s. KDPI genes were expressed differentially in four developmental stages of the worm. Transcription analysis showed that 9 KDPIs (including EG_07244,EGR_08716 and EGR_10096) were highly upregulated in adult worm, and 2 KDPIs (EG_09268 and EG_09490) were highly expressed in the cyst germinal membrane. Quantitative gene expression analysis(qPCR) of four genes confirmed the expression of these genes. EGR_08716 and its homologous gene (EmuJ_001137000) were highly and specifically expressed in adult worms of the two worms.ConclusionsA total 19 and 23 KDPIs were identified in the genomes of E. multilocularis and E. granulosus s.s. , respectively. The differential expression of these KDPIs in different stages may indicate their different roles in the different hosts. The difference in characterization of KDPIs may be associated with the different pathology of metacestode stage of these two parasites.

Dataset Information

Kunitz type protease inhibitor EgKI-1 from the canine tapeworm Echinococcus granulosus as a promising therapeutic against breast cancer.

Publications

Kunitz type protease inhibitor EgKI-1 from the canine tapeworm Echinococcus granulosus as a promising therapeutic against breast cancer.

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