Developing natural products and dietary supplements has proven to be a promising strategy for the cancer therapy and prevention. Among them, fucoidan, which is isolated from brown seaweed such as Cladosiphon okamuranus and Fucus evanescens (1, 2), is structurally similar to heparin, with a substantial percentage of L-fucose (3, 4). Recent studies have shown its various effects on biological activities such as antiinflammatory, anti-coagulant (5), anti-HIV, and anticancer (6-9) activities. With respect to cancer therapy, fucoidan appears to be highly efficient in treating certain types of cancer, including breast, prostate and lung, as well as leukemia (10-12). Furthermore, fucoidan can also play a crucial role in inhibiting induced cancer signaling molecules, such as vascular endothelial growth factor (VEGF) (13,14). Although these results support the potential development of fucoidan as an anticancer drug, there is little information on the anticancer effect of fucoidan on colorectal cancer (CRC).CRC is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite continuous progress in developing diagnostic and therapeutic methods (15). It is thought that CRC may be caused by a combination of both genetic susceptibilities and Iifestyle factors such as a meat-rich diet (16). Although the discovery of factors that cause CRC give new insights into the growth and metastasis of CRC, there is still little information on the etiology of most CRC, therapeutic agents, and anti-CRC targeting molecules. However, cellular prion protein (PrP c ) expression has been identified as a risk or susceptibility factor for developing CRC (17). In essence, PrP c is a highly conserved cell-surface glycoprotein that has been identified in all vertebrates, with the same protein sequence as the prion proteins that cause 4449
Cripto is a small glycosylphosphatidylinositol-anchored signaling protein that can detach from the anchored membrane and stimulate proliferation, migration, differentiation, vascularization, and angiogenesis. In the present study, we demonstrated that Cripto positively affected proliferation and survival of mesenchymal stem cells (MSCs) without affecting multipotency. Cripto also increased expression of phosphorylated janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), 78 kDa glucose-regulated protein (GRP78), c-Myc, and cyclin D1. Notably, treatment with an anti-GRP78 antibody blocked these effects. In addition, pretreatment with STAT3 short interfering RNA (siRNA) inhibited the increase in p-JAK2, c-Myc, cyclin D1, and BCL3 levels caused by Cripto and attenuated the pro-survival action of Cripto on MSCs. We also found that incubation with Cripto protected MSCs from apoptosis caused by hypoxia or H2O2 exposure, and the level of caspase-3 decreased by the Cripto-induced expression of B-cell lymphoma 3-encoded protein (BCL3). These effects were sensitive to down-regulation of BCL3 expression by BCL3 siRNA. Finally, we showed that Cripto enhanced expression levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF). In summary, our results demonstrated that Cripto activated a novel biochemical cascade that potentiated MSC proliferation and survival. This cascade relied on phosphorylation of JAK2 and STAT3 and was regulated by GRP78. Our findings may facilitate clinical applications of MSCs, as these cells may benefit from positive effects of Cripto on their survival and biological properties.
Glucocerebrosidase (GCase) functions as a lysosomal enzyme and its mutations are known to be related to many neurodegenerative diseases, including Gaucher’s disease (GD), Parkinson’s disease (PD), and Dementia with Lewy Bodies (DLB). However, there is little information about the role of GCase in the pathogenesis of Alzheimer’s disease (AD). Here we demonstrate that GCase protein levels and enzyme activity are significantly decreased in sporadic AD. Moreover, Aβ1–42 oligomer treatment results in neuronal cell death that is concomitant with decreased GCase protein levels and enzyme activity, as well as impairment in lysosomal biogenesis and acidification. Importantly, overexpression of GCase promotes the lysosomal degradation of Aβ1–42 oligomers, restores the lysosomal impairment, and protects against the toxicity in neurons treated with Aβ1–42 oligomers. Our findings indicate that a deficiency of GCase could be involved in progression of AD pathology and suggest that augmentation of GCase activity may be a potential therapeutic option for the treatment of AD.
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