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Fucoidan, a polysaccharide extracted from brown seaweeds, reduces tumor cell proliferation. Fucoidan inhibits the growth of breast cancer cells such as 4T1 and MDA-MB-231 and decreases their cell colony formation. Moreover, fucoidan reduces metastatic lung nodules in 4T1 xenograft female Balb/c mice. The molecular network of transforming growth factor β (TGFβ) receptors (TGFRs) plays an important role in the regulation of the epithelial to mesenchymal transition (EMT) in cancer cells. Using 4T1 and MDA-MB-231 cells, we found that fucoidan effectively reverses TGFR-induced EMT morphological changes, upregulates epithelial markers, downregulates mesenchymal markers and decreases the expression of transcriptional repressors Snail, Slug and Twist. Moreover, fucoidan inhibits migration and invasion during the EMT, suggesting the involvement of TGFR-mediated signaling in breast cancer cells. Fucoidan decreases TGFRI and TGFRII proteins and affects downstream signaling molecules, including Smad2/3 phosphorylation and Smad4 expression. In order to elucidate how fucoidan decreases TGFRI and TGFRII proteins in MDA-MB-231 cells, we investigated ubiquitination activity downregulation of TGFRs. It was found that fucoidan enhances proteasome-mediated degradation/ubiquitination of TGFR. This study is the first to identify a novel mechanism for fucoidan antitumor activity, namely regulation of the EMT via modulation of TGFR/Smad-dependent signaling, which leads to an inhibition of breast cancer cell growth in vitro and in vivo. Our current findings indicate that fucoidan is a potential therapeutic agent for breast cancer and acts via an ubiquitin-dependent degradation pathway that affects the TGFR/Smad/Snail, Slug, Twist and EMT axes.

2020) BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells, Autophagy, 16:7, 1296-1313, ABSTRACT BIRC5/Survivin is known as a dual cellular functions protein that directly regulates both apoptosis and mitosis in embryonic cells during embryogenesis and in cancer cells during tumorigenesis and tumor metastasis. However, BIRC5 has seldom been demonstrated as a direct macroautophagy/autophagy regulator in cells. ATG7 expression and ATG12-ATG5-ATG16L1 complex formation are crucial for the phagophore elongation during autophagy in mammalian cells. In this study, we observed that the protein expression levels of BIRC5 and ATG7 were inversely correlated, whereas the expression levels of BIRC5 and SQSTM1/p62 were positively correlated in normal breast tissues and tumor tissues. Mechanistically, we found that BIRC5 negatively modulates the protein stability of ATG7 and physically binds to the ATG12-ATG5 conjugate, preventing the formation of the ATG12-ATG5-ATG16L1 protein complex in human cancer (MDA-MB-231, MCF7, and A549) and mouse embryonic fibroblast (MEF) cells. We also observed a concurrent physical dissociation between BIRC5 and ATG12-ATG5 (but not CASP3/caspase-3) and upregulation of autophagy in MDA-MB-231 and A549 cells under serum-deprived conditions. Importantly, despite the fact that upregulation of autophagy is widely thought to promote DNA repair in cells under genotoxic stress, we found that BIRC5 maintains DNA integrity through autophagy negative-modulations in both human cancer and MEF cells under non-stressed conditions. In conclusion, our study reveals a novel role of BIRC5 in cancer cells as a direct regulator of autophagy. BIRC5 may act as a "bridging molecule", which regulates the interplay between mitosis, apoptosis, and autophagy in embryonic and cancer cells.

SynopsisThe content of acrylic acid and acrylamide in their copolymers can be controlled by changing pH. The reactivity ratio of acrylic acid decreases with increasing pH, while the reactivity ratio of acrylamide increases with increasing pH. At low pH values, acrylamide is present in its protonated form which causes its reactivity to be low whereas at high pH vahies the reactivity of acrylic acid is decreased owing to its dissociation. When the monomer and radical approach each other, the acrylate anion becomes the least reactive species because of its symmetrical charge distribution, like charge repulsion and barium ion screening effect. HMO calculations were performed for models of all monomers and polymer radicals involved in copolymerizations. The experimental results concerning the reactivity of acrylic acid and acrylamide in copolymerization and the observed reactivity ratios were discussed on the basis of HMO calculations and resonance and Coulomb electrostatic effects. The observed reactivity ratios were correlated with the calculated differences in resonance energies computed for the models of transition states involved in copolymerizations.

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X-linked inhibitor of apoptosis protein (XIAP), survivin, and BRUCE are members of the inhibitor-of-apoptosis protein (IAP) family known for their inhibitory effects on caspase activity and dysregulation of these molecules has widely been shown to cause embryonic defects and to promote tumorigenesis in human. Besides the anti-apoptotic functions, recent discoveries have revealed that XIAP, survivin, and BRUCE also exhibit regulatory functions for autophagy in cells. As the role of autophagy in human diseases has already been discussed extensively in different reviews; in this review, we will discuss the emerging autophagic role of XIAP, survivin, and BRUCE in cancer cells. We also provide an update on the anti-apoptotic functions and the roles in maintaining DNA integrity of these molecules. Second mitochondria-derived activator of caspases (Smac) is a pro-apoptotic protein and IAPs are the molecular targets of various Smac mimetics currently under clinical trials. Better understanding on the functions of XIAP, survivin, and BRUCE can enable us to predict possible side effects of these drugs and to design a more "patient-specific" clinical trial for Smac mimetics in the future.

Carbohydrate-based vaccines have shown therapeutic efficacy for infectious disease and cancer. The mushroom Ganoderma lucidum (Reishi) containing complex polysaccharides has been used as antitumor supplement, but the mechanism of immune response has rarely been studied. Here, we show that the mice immunized with a L-fucose (Fuc)-enriched Reishi polysaccharide fraction (designated as FMS) induce antibodies against murine Lewis lung carcinoma cells, with increased antibody-mediated cytotoxicity and reduced production of tumor-associated inflammatory mediators (in particular, monocyte chemoattractant protein-1). The mice showed a significant increase in the peritoneal B1 B-cell population, suggesting FMS-mediated anti-glycan IgM production. Furthermore, the glycan microarray analysis of FMS-induced antisera displayed a high specificity toward tumor-associated glycans, with the antigenic structure located in the nonreducing termini (i.e., Fucα1-2Galβ1-3GalNAc-R, where Gal, GalNAc, and R represent, respectively, Dgalactose, D-N-acetyl galactosamine, and reducing end), typically found in Globo H and related tumor antigens. The composition of FMS contains mainly the backbone of 1,4-mannan and 1,6-α-galactan and through the Fucα1-2Gal, Fucα1-3/4Man, Fucα1-4Xyl, and Fucα1-2Fuc linkages (where Man and Xyl represent D-mannose and D-xylose, respectively), underlying the molecular basis of the FMSinduced IgM antibodies against tumor-specific glycans. mushroom polysaccharide | antitumor activity | anti-Globo H antibody V arious forms of herbal medicine polysaccharides have become valuable as health supplements worldwide (1, 2), suggesting that administration of such polysaccharides may improve innate immunity in vivo. The underlying molecular mechanisms, however, still remain ambiguous. Aberrant terminal fucosylation as well as sialylation in tumor-associated glycans is one of several glycosylation events important in cancer progression (3, 4), and such unusual glycans have recently been used for the development of anticancer vaccines (5-7). As an example, the Globo H-based glycoconjugate vaccines are currently undergoing large-scale clinical trials and have shown promise in therapeutic treatment (8, 9). Studies on the immune response to pathogenic microorganisms (such as Haemophilus influenza type B and Streptococcus pneumonia) have demonstrated that polysaccharides containing repeating antigenic units are generally T cell-independent (TI) (10, 11). Furthermore, recent findings revealed that specific B-cell subsets could establish memory for providing specific Ig synthesis in response to TI-associated polysaccharides (12)(13)(14). In an attempt to understand the biological significance of polysaccharides derived from natural sources, we previously isolated and characterized a crude extract fraction of water-soluble and L-fucose (Fuc)-containing polysaccharides (F3) from Ganoderma lucidum (Reishi) (a mushroom that has been long used as a herb medicine) (15). F3 has since been shown essential for regulation of cytokine network...

The skin provides protection against external stimuli; however, solar radiation, including ultraviolet A (UVA) and ultraviolet B (UVB), can result in profound influences on skin structure and function, which eventually impairs its molecular characteristics and normal physiology. In the current study, we performed proteome tools combined with an immunohistological approach on nude mouse skin to evaluate the adverse responses elicited by UVA and UVB irradiation, respectively. Our findings indicated that UVA significantly promotes oxidative damage in DNA, the breakdown of collagen fiber in the dermis, and the apoptosis of fibroblasts, which leads to inflammation. Meanwhile, UVB administration was found to enhance the carbonylation of various proteins and the proliferation of keratinocyte. Particularly, raspberry extract, which has been confirmed to have antioxidative efficacy, could effectively attenuate ultraviolet (UV) radiation-caused cell death. Network analysis also implied that UVA and UVB induce quite different responses, and that UVA results in cell death as well as inflammation mediated by caspase-3 and activator protein 1/nuclear factor kappa-light-chain-enhancer of activated B cells (AP-1/NF-κB), while UVB predominantly increases the risk of skin carcinogenesis involved with oncogenes such as p53 and c-Myc. Taken together, functional proteomics coordinated with histological experiments could allow for a high-throughput study to explore the alterations of crucial proteins and molecules linked to skin impacts subjected to UVA and UVB exposure.