Riproximin Exhibits Diversity in Sugar Binding, and Modulates Some Metastasis-Related Proteins with Lectin Like Properties in Pancreatic Ductal Adenocarcinoma
Loading...
Date
2020
Authors
Sagini, Micah N
Klika, Karel D
Orry, Andrew
Zepp, Michael
Mutiso, Joshua
Berger, Martin R
Journal Title
Journal ISSN
Volume Title
Publisher
Frontiers Media SA
Abstract
termed lactosyl-sepharose binding proteins (LSBPs). The role of these proteins in
cancer progression was investigated at mRNA level using chip array data of Suit2-007 and
ASML cells re-isolated from nude rats. These data compared significant mRNA expression
changes when relating primary (pancreas) and metastatic (liver) sites following orthotopic
and intraportal implantation of Pancreatic Ductal Adenocarcinoma (PDAC) cells,
respectively. The affinity of Rpx to 13 simple sugar structures was modeled by
docking experiments, the ranking of which was principally confirmed by NMRspectroscopy. In addition, Rpx and LSBPs were evaluated for anti-proliferative activity
and their cellular uptake was assessed by fluorescence microscopy. From 13
monosaccharides evaluated, open-chain rhamnose, β-D-galactose, and
α-L-galactopyranose showed the highest affinities for site 1 of Rpx’s B-chain. NMR
evaluation yielded a similar ranking, as galactose was among the best binders. Both,
Rpx and LSBPs reduced cell proliferation in vitro, but their anti-proliferative effects were
decreased by 15–20% in the presence of galactose. The program “Ingenuity Pathway
Analysis” identified 2,415 genes showing significantly modulated mRNA expression
following exposure of Suit2-007 cells to Rpx in vitro. These genes were then matched
to those 1,639 genes, which were significantly modulated in the rat model when
comparing primary and metastatic growth of Suit2-007 cells. In this overlap analysis,
LSBP genes were considered separately. The potential suitability of Rpx for treating
metastatic Suit2-007 PDAC cells was reflected by those genes, which were modulated by
Rpx in a way opposite to that observed in cancer progression. Remarkably, these were
14% of all genes modulated during cancer progression, but 71% of the respective LSBP
gene subgroup. Based on these findings, we predict that Rpx has the potential to treat
PDAC metastasis by modulating genes involved in metastatic progression, especially by
targeting LSBPs
Description
Article
Keywords
Pancreatic ductal adenocarcinoma, lactosyl-sepharose binding proteins, cellular lectins, ribosomeinactivating protein, monosaccharides, affinity
Citation
Sagini, M. N., Klika, K. D., Orry, A., Zepp, M., Mutiso, J., & Berger, M. R. (2020). Riproximin exhibits diversity in sugar binding, and modulates some metastasis-related proteins with lectin like properties in pancreatic ductal adenocarcinoma. Frontiers in pharmacology, 11, 549804.