This review is intended for general readers who would like a basic foundation in carbohydrate structure and function, lectin biology and the implications of glycobiology in human health and disease, particularly in cancer therapeutics. These topics are among the hundreds included in the field of glycobiology and are treated here because they form the cornerstone of glycobiology or the focus of many advances in this rapidly expanding field.
BackgroundDrug resistance of B-cell precursor acute lymphoblastic leukemia (BP-ALL) cells is conferred by both intrinsic and extrinsic factors, which could be targeted to promote chemo-sensitization. Our previous studies showed that Galectin-3, a lectin that clusters galactose-modified glycoproteins and that has both an intracellular and extracellular location, protects different subtypes of BP-ALL cells against chemotherapy. Galectin-1 is related to Galectin-3 and its expression was previously reported to be restricted to the MLL subtype of BP-ALL.Methods and resultsHere, we report that Galectin-1 is expressed at different levels in and on different subclasses of BP-ALLs. Bone marrow plasma also contains high levels of Galectin-1. PTX008 is an allosteric inhibitor which inhibits Galectin-1 but not Galectin-3-mediated agglutination. The compound reduces migration of BP-ALL cells to CXCL12 and OP9 stromal cells and inhibits fibronectin-mediated adhesion. It also affects cell cycle progression of BCP-ALL cells. PTX008 is cytostatic for BP-ALL cells even when these are co-cultured with protective stroma, and can sensitize ALL cells to vincristine chemotherapy in vitro and in mice.ConclusionsPTX008 inhibits multiple functions that contribute to BP-ALL survival. The effects of Galectin-1 inhibition on both BP-ALL cell proliferation and migration suggest both the leukemia cells as well as the microenvironment that protects these cells may be targeted.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0721-7) contains supplementary material, which is available to authorized users.
We present an unusual and novel model for initial investigations of a putative role for specifically conformed glycans in cellular interactions. We have used α-and ß-amylase and α-and ß-glucosidase in dose-response experiments evaluating their effects on archenteron organization using the NIH designated sea urchin embryo model. In quantitative dose-response experiments, we show that defined activity levels of α-glucosidase and ß-amylase inhibited archenteron organization in living Lytechinus pictus gastrula embryos, whereas all concentrations of ß-glucosidase and α-amylase were without substantial effects on development. Product inhibition studies suggested that the enzymes were acting by their specific glycosidase activities and polyacrylamide gel electrophoresis suggested that there was no detectable protease contamination in the active enzyme samples. The results provide evidence for a role of glycans in sea urchin embryo cellular interactions with special reference to the possible structural conformation of these glycans based on the differential activities of the α-and ß-glycosidases.
SummaryIn Strongylocentrotus purpuratus the hyalins are a set of three to four rather large glycoproteins (hereafter referred to as "hyalin"), which are the major constituents of the hyaline layer, the developing sea urchin embryo's extracellular matrix. Recent research from our laboratories has shown that hyalin is a cell adhesion molecule involved in sea urchin embryo specific cellular interactions. Other laboratories have shown it to consist of 2-3% carbohydrate, and a cloned, sequenced fragment demonstrated repeat domains (HYR) and non-repeat regions. Interest in this molecule has increased because HYR has been identified in organisms as diverse as bacteria, flies, worms, mice and humans, as well as sea urchins. Our laboratories have shown that hyalin appears to mediate a specific cellular interaction that has interested investigators for over a century, archenteron elongation/attachment to the blastocoel roof. We have done this by localizing hyalin on the two components of the cellular interaction and by showing that hyalin and anti-hyalin antibody block the cellular interaction using a quantitative microplate assay. The microplate assay, however, has limitations because it does not directly assess hyalin's effects on the adhesion of the two components of the interaction. Here we have used an elegant direct assay that avoids the limitations, where we microdissected the two components of the adhesive interaction and tested their readhesion to each other, thereby avoiding possible factors in the whole embryos that could confound or confuse results. Using both assays, we found that mild periodate treatment (6 h to 24 h in sodium acetate buffer with 0.2M sodium periodate at 4 °C in the dark) of hyalin eliminates its ability to block the cellular interaction, suggesting that the carbohydrate component(s) may be involved in hyalin's specific adhesive function. This is an important first step in identifying the molecular mechanisms of a well known cellular interaction in the NIH designated sea urchin embryo model, a system that has led to the discovery of scores of physiological mechanisms, including those involved in human health and disease.
Periodate oxidation has been widely used to degrade the carbohydrate components of molecules to help determine the role of sugars in molecular function. In this study, 24.5‐26 hr early gastrula Lytechinus pictus sea urchin embryos were incubated with specific ultra‐low concentrations of sodium (meta) periodate that degrades some carbohydrates by selectively oxidizing C‐C bonds between vicinal diols. Incubations were carried out in 15 degrees C artificial seawater in 96 well microplates for 24‐25 hrs. After the incubation period, embryos were examined for viability, fixed in 5% formaldehyde, and the morphological characteristics of 5664 embryos were quantitatively assessed as embryos possessing complete attached archenterons, incomplete unattached archenterons, no invagination, exogastrulation, or embryos that were dead. At 1.2x10−6 ‐3.9x10−5 mg periodate/ml 15‐30% of the embryos were swimming and possessed incomplete unattached archenterons, while the controls without periodate displayed 2.3% incomplete archenterons. At higher concentrations of periodate (7.8x10−5‐1.0x10−2 mg periodate/ml), embryo death occurred. Using a two‐sample equal variances t‐test, the numbers of unattached archenterons in the 1.2x10−6‐3.9 x10−5 mg periodate/ml treated embryos were significantly different from those in the controls without periodate at a p value of less than 0.001. The use of periodate in probing whole, living embryos is novel and could become widely used to help identify the role of glycans in interacting systems (Supported by NIH NIGMS SCORE (S0648680), MARC, RISE, the Joseph Drown Foundation, and the Sidney Stern Memorial Trust).
Hyalin (Hy), a set of large glycoproteins containing 2‐3% carbohydrate appears to be a specific cell adhesion molecule in the sea urchin embryo model. Sodium (meta) periodate (PI) can selectively degrade carbohydrate by oxidizing the C‐C bonds between vicinal diols. Untreated Strongylocentrotus purpuratus Hy blocked the adhesion of the tip of the archenteron to the roof of the blastocoel (the specific adhesive interaction under study) in two assays: (1) a microplate assay using live Lytechinus pictus embryos and (2) using dissected pieces of the archenteron and blastocoel roof. Hy cross reacts between these two species. PI treated Hy did not block this interaction in either assay. The microplate analysis, with over 16,000 L. pictus embryos, indicated that 6 hr PI treated Hy (0.17‐0.34 mg treated Hy/ml low calcium artificial sea water ‐LCSW) did not block the cellular interaction, while untreated Hy (0.17‐0.34 mg untreated Hy/ml LCSW) did. 76.4‐77.2% ± 2% of the embryos in PI treated Hy possessed complete archenterons, while 2.7‐7.6% ± 12% possessed complete archenterons in the untreated Hy samples with a p value of less than 0.001. Similar results were obtained using the dissected pieces assay. While this study suggests that Hy carbohydrate is involved in Hy function, further studies are needed to determine if PI is also affecting Hy in other ways (Supported by NIH NIGMS SCORE (S0648680), MARC, RISE, the Joseph Drown Foundation and the Sidney Stern Memorial Trust).
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