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Protein-bound polysaccharide from Phellinus linteus inhibits tumor growth, invasion, and angiogenesis and alters Wnt/β-catenin in SW480 human colon cancer cells
Kyoung-Sub Song, Ge Li, Jong-Seok Kim, Kaipeng Jing, Tae-Dong Kim, Jin-Pyo Kim, Seung-Bo Seo, Jae-Kuk Yoo, Hae-Duck Park, Byung-Doo Hwang, Kyu Lim, Wan-Hee Yoon
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-307
Abstract: The anti-cancer effects of PL were examined in SW480 colon cancer cells by evaluating cell proliferation, invasion and matrix metallo-proteinase (MMP) activity. The anti-angiogenic effects of PL were examined by assessing human umbilical vein endothelial cell (HUVEC) proliferation and capillary tube formation. The in vivo effect of PL was evaluated in an athymic nude mouse SW480 tumor engraft model.PL (125-1000 μg/mL) significantly inhibited cell proliferation and decreased β-catenin expression in SW480 cells. Expression of cyclin D1, one of the downstream-regulated genes of β-catenin, and T-cell factor/lymphocyte enhancer binding factor (TCF/LEF) transcription activity were also significantly reduced by PL treatment. PL inhibited in vitro invasion and motility as well as the activity of MMP-9. In addition, PL treatment inhibited HUVEC proliferation and capillary tube formation. Tumor growth of SW480 cells implanted into nude mice was significantly decreased as a consequence of PL treatment, and tumor tissues from treated animals showed an increase in the apoptotic index and a decrease in β-catenin expression. Moreover, the proliferation index and microvessel density were significantly decreased.These data suggest that PL suppresses tumor growth, invasion, and angiogenesis through the inhibition of Wnt/β-catenin signaling in certain colon cancer cells.Colorectal cancer (CRC) is the third most prevalent form of cancer in men and women, with a 5-year survival rate of 63%, decreasing to 10% in patients with metastatic disease [1]. Thus, the formation of distant metastasis is the decisive and most lethal event during the course of the disease. Although recent advances in chemotherapeutic agents in CRC have been achieved, treatment options are still limited and are associated with significant morbidity and mortality.Mushroom polysaccharides are widely being used as nonspecific immunostimulants for cancer patients in Asian countries. The Polysaccharide isolated from Phell
The function of BCL9 in Wnt/β-catenin signaling and colorectal cancer cells
Marc de la Roche, Jesper Worm, Mariann Bienz
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-199
Abstract: We have used overexpression of dominant-negative forms of BCL9, and RNAi-mediated depletion, to study its function in human cell lines with elevated Wnt pathway activity, including colorectal cancer cells.We found that BCL9 is required for efficient β-catenin-mediated transcription in Wnt-stimulated HEK 293 cells, and in the SW480 colorectal cancer cell line whose Wnt pathway is active due to APC mutation. Dominant-negative mutants of BCL9 indicated that its function depends not only on its β-catenin ligand, but also on an unknown ligand of its C-terminus. Finally, we show that BCL9 and B9L are both Wnt-inducible genes, hyperexpressed in colorectal cancer cell lines, indicating that they are part of a positive feedback loop.BCL9 is required for efficient β-catenin-mediated transcription in human cell lines whose Wnt pathway is active, including colorectal cancer cells, indicating its potential as a drug target in colorectal cancer.The canonical Wnt signaling pathway changes the transcriptional program of cells, and controls genes with important functions during normal and malignant development [1-3]. A key effector of this pathway is β-catenin, which is normally phosphorylated and targeted for degradation by the Axin complex that also contains the Adenomatous polyposis coli (APC) tumor suppressor. This complex is inhibited in response to Wnt stimulation, allowing unphosphorylated β-catenin to accumulate and bind to the nuclear TCF/LEF factors to stimulate the transcription of Wnt target genes. This trans-activation function of β-catenin involves the recruitment of a range of different co-factors that bind to its C-terminus, including chromatin modifying and remodelling factors such as CBP, Brg-1 and SET1 [4-10], TATA-binding protein and associated factors [11,12], and also a transcriptional elongation factor [13]. Well-established transcriptional target genes of this pathway include c-myc, AXIN2 and CD44, whose expression is upregulated in a TCF-dependent fashion in
Hsp90 Inhibition Decreases Mitochondrial Protein Turnover  [PDF]
Daciana H. Margineantu, Christine B. Emerson, Dolores Diaz, David M. Hockenbery
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0001066
Abstract: Background Cells treated with hsp90 inhibitors exhibit pleiotropic changes, including an expansion of the mitochondrial compartment, accompanied by mitochondrial fragmentation and condensed mitochondrial morphology, with ultimate compromise of mitochondrial integrity and apoptosis. Findings We identified several mitochondrial oxidative phosphorylation complex subunits, including several encoded by mtDNA, that are upregulated by hsp90 inhibitors, without corresponding changes in mRNA abundance. Post-transcriptional accumulation of mitochondrial proteins observed with hsp90 inhibitors is also seen in cells treated with proteasome inhibitors. Detailed studies of the OSCP subunit of mitochondrial F1F0-ATPase revealed the presence of mono- and polyubiquitinated OSCP in mitochondrial fractions. We demonstrate that processed OSCP undergoes retrotranslocation to a trypsin-sensitive form associated with the outer mitochondrial membrane. Inhibition of proteasome or hsp90 function results in accumulation of both correctly targeted and retrotranslocated mitochondrial OSCP. Conclusions Cytosolic turnover of mitochondrial proteins demonstrates a novel connection between mitochondrial and cytosolic compartments through the ubiquitin-proteasome system. Analogous to defective protein folding in the endoplasmic reticulum, a mitochondrial unfolded protein response may play a role in the apoptotic effects of hsp90 and proteasome inhibitors.
Canonical Wnt signaling protects hippocampal neurons from Aβ oligomers: role of non-canonical Wnt-5a/Ca2+ in mitochondrial dynamics  [PDF]
Carmen Silva-Alvarez,Juan A. Godoy,Daniela Ordenes,Nibaldo C. Inestrosa
Frontiers in Cellular Neuroscience , 2013, DOI: 10.3389/fncel.2013.00097
Abstract: Alzheimer's disease (AD) is the most common type of age-related dementia. The disease is characterized by a progressive loss of cognitive abilities, severe neurodegeneration, synaptic loss and mitochondrial dysfunction. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulate the function of the adult nervous system. We report here, that indirect activation of canonical Wnt/β-catenin signaling using Bromoindirubin-30-Oxime (6-BIO), an inhibitor of glycogen synthase kinase-3β, protects hippocampal neurons from amyloid-β (Aβ) oligomers with the concomitant blockade of neuronal apoptosis. More importantly, activation with Wnt-5a, a non-canonical Wnt ligand, results in the modulation of mitochondrial dynamics, preventing the changes induced by Aβ oligomers (Aβo) in mitochondrial fission-fusion dynamics and modulates Bcl-2 increases induced by oligomers. The canonical Wnt-3a ligand neither the secreted Frizzled-Related Protein (sFRP), a Wnt scavenger, did not prevent these effects. In contrast, some of the Aβ oligomer effects were blocked by Ryanodine. We conclude that canonical Wnt/β-catenin signaling controls neuronal survival, and that non-canonical Wnt/Ca2+signaling modulates mitochondrial dysfunction. Since mitochondrial dysfunction is present in neurodegenerative diseases, the therapeutic possibilities of the activation of Wnt signaling are evident.
Multiple major increases and decreases in mitochondrial substitution rates in the plant family Geraniaceae
Christopher L Parkinson, Jeffrey P Mower, Yin-Long Qiu, Andrew J Shirk, Keming Song, Nelson D Young, Claude W dePamphilis, Jeffrey D Palmer
BMC Evolutionary Biology , 2005, DOI: 10.1186/1471-2148-5-73
Abstract: We explored a second potential case of highly accelerated mitochondrial sequence evolution in plants. This case was first suggested by relatively poor hybridization of mitochondrial gene probes to DNA of Pelargonium hortorum (the common geranium). We found that all eight mitochondrial genes sequenced from P. hortorum are exceptionally divergent, whereas chloroplast and nuclear divergence is unexceptional in P. hortorum. Two mitochondrial genes were sequenced from a broad range of taxa of variable relatedness to P. hortorum, and absolute rates of mitochondrial synonymous substitutions were calculated on each branch of a phylogenetic tree of these taxa. We infer one major, ~10-fold increase in the mitochondrial synonymous substitution rate at the base of the Pelargonium family Geraniaceae, and a subsequent ~10-fold rate increase early in the evolution of Pelargonium. We also infer several moderate to major rate decreases following these initial rate increases, such that the mitochondrial substitution rate has returned to normally low levels in many members of the Geraniaceae. Finally, we find unusually little RNA editing of Geraniaceae mitochondrial genes, suggesting high levels of retroprocessing in their history.The existence of major, mitochondrial-specific changes in rates of synonymous substitutions in the Geraniaceae implies major and reversible underlying changes in the mitochondrial mutation rate in this family. Together with the recent report of a similar pattern of rate heterogeneity in Plantago, these findings indicate that the mitochondrial mutation rate is a more plastic character in plants than previously realized. Many molecular factors could be responsible for these dramatic changes in the mitochondrial mutation rate, including nuclear gene mutations affecting the fidelity and efficacy of mitochondrial DNA replication and/or repair and – consistent with the lack of RNA editing – exceptionally high levels of "mutagenic" retroprocessing. That the mitocho
Wnt1 Neuroprotection Translates into Improved Neurological Function during Oxidant Stress and Cerebral Ischemia Through AKT1 and Mitochondrial Apoptotic Pathways  [PDF]
Zhao Zhong Chong,Yan Chen Shang,Jinling Hou,Kenneth Maiese
Oxidative Medicine and Cellular Longevity , 2010, DOI: 10.4161/oxim.3.2.11758
Abstract: Although essential for the development of the nervous system, Wnt1 also has been associated with neurodegenerative disease and cognitive loss during periods of oxidative stress. Here we show that endogenous expression of Wnt1 is suppressed during oxidative stress in both in vitro and in vivo experimental models. Loss of endogenous Wnt1 signaling directly correlates with neuronal demise and increased functional deficit, illustrating that endogenous neuronal Wnt1 offers a vital level of intrinsic cellular protection against oxidative stress. Furthermore, transient overexpression of Wnt1 or application of exogenous Wnt1 recombinant protein is necessary to preserve neurological function and rescue neurons from apoptotic membrane phosphatidylserine externalization and genomic DNA degradation, since blockade of Wnt1 signaling with a Wnt1 antibody or dickkopf related protein 1 abrogates neuronal protection by Wnt1. Wnt1 ultimately relies upon the activation of Akt1, the modulation of mitochondrial membrane permeability, and the release of cytochrome c to control the apoptotic cascade, since inhibition of Wnt1 signaling, the phosphatidylinositol 3-kinase pathway, or Akt1 activity abrogates the ability of Wnt1 to block these apoptotic components. Our work identifies Wnt1 and its downstream signaling as cellular targets with high clinical potential for novel treatment strategies for multiple disorders precipitated by oxidative stress.
Wnt1 Neuroprotection Translates into Improved Neurological Function during Oxidant Stress and Cerebral Ischemia Through AKT1 and Mitochondrial Apoptotic Pathways  [PDF]
Zhao Zhong Chong,Yan Chen Shang,Jinling Hou,Kenneth Maiese
Oxidative Medicine and Cellular Longevity , 2010, DOI: 10.4161/oxim.3.2.11758
Abstract: Although essential for the development of the nervous system, Wnt1 also has been associated with neurodegenerative disease and cognitive loss during periods of oxidative stress. Here we show that endogenous expression of Wnt1 is suppressed during oxidative stress in both in vitro and in vivo experimental models. Loss of endogenous Wnt1 signaling directly correlates with neuronal demise and increased functional deficit, illustrating that endogenous neuronal Wnt1 offers a vital level of intrinsic cellular protection against oxidative stress. Furthermore, transient overexpression of Wnt1 or application of exogenous Wnt1 recombinant protein is necessary to preserve neurological function and rescue neurons from apoptotic membrane phosphatidylserine externalization and genomic DNA degradation, since blockade of Wnt1 signaling with a Wnt1 antibody or dickkopf related protein 1 abrogates neuronal protection by Wnt1. Wnt1 ultimately relies upon the activation of Akt1, the modulation of mitochondrial membrane permeability, and the release of cytochrome c to control the apoptotic cascade, since inhibition of Wnt1 signaling, the phosphatidylinositol 3-kinase pathway, or Akt1 activity abrogates the ability of Wnt1 to block these apoptotic components. Our work identifies Wnt1 and its downstream signaling as cellular targets with high clinical potential for novel treatment strategies for multiple disorders precipitated by oxidative stress.
The Non-Canonical Wnt/PKC Pathway Regulates Mitochondrial Dynamics through Degradation of the Arm-Like Domain-Containing Protein Alex3  [PDF]
Román Serrat, Guillermo López-Doménech, Serena Mirra, Martí Quevedo, Jordi Garcia-Fernàndez, Fausto Ulloa, Ferrán Burgaya, Eduardo Soriano
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0067773
Abstract: The regulation of mitochondrial dynamics is vital in complex cell types, such as neurons, that transport and localize mitochondria in high energy-demanding cell domains. The Armcx3 gene encodes a mitochondrial-targeted protein (Alex3) that contains several arm-like domains. In a previous study we showed that Alex3 protein regulates mitochondrial aggregation and trafficking. Here we studied the contribution of Wnt proteins to the mitochondrial aggregation and dynamics regulated by Alex3. Overexpression of Alex3 in HEK293 cells caused a marked aggregation of mitochondria, which was attenuated by treatment with several Wnts. We also found that this decrease was caused by Alex3 degradation induced by Wnts. While the Wnt canonical pathway did not alter the pattern of mitochondrial aggregation induced by Alex3, we observed that the Wnt/PKC non-canonical pathway regulated both mitochondrial aggregation and Alex3 protein levels, thereby rendering a mitochondrial phenotype and distribution similar to control patterns. Our data suggest that the Wnt pathway regulates mitochondrial distribution and dynamics through Alex3 protein degradation.
High Expression of IGFBP7 in Fibroblasts Induced by Colorectal Cancer Cells Is Co-Regulated by TGF-β and Wnt Signaling in a Smad2/3-Dvl2/3-Dependent Manner  [PDF]
Cui Rao, Shan-Li Lin, Wen-Jing Ruan, Huan Wen, Dan-Ju Wu, Hong Deng
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085340
Abstract: Fibroblasts in the tumor microenvironment are a key determinant in cancer progression and may be a promising target for cancer therapy. Insulin-like growth factor binding protein 7 (IGFBP7) is known as a tumor suppressor in colorectal cancer (CRC). The present study investigated the inductive mechanism of IGFBP7 expression in fibroblasts by supernatant from the CRC cell line, SW620. The results showed that the expression of IGFBP7 was up-regulated in the fibroblasts when treated with SW620 supernatant and exogenous TGF-β1. The IGFBP7 induced by SW620 supernatant or TGF-β1 was partially inhibited by the TGF-β1 specific antibody AF and TGF-β1 receptor antagonist SB431542. The Wnt signaling-targeted genes, c-Myc, CCND1 and the proteins Dvl2/3, were all up-regulated in fibroblasts expressing high levels of IGFBP7, and the up-regulation could be inhibited both by the Wnt signaling antagonist Dickkopf-1 (DKK1) and by the TGF-β1 receptor antagonist SB431542. In conclusion, CRC cells promote the high expression of IGFBP7 in fibroblasts, most likely through the co-regulation of TGF-β and Wnt signaling in a Smad2/3-Dvl2/3 dependent manner. Taken together, these data suggest that the fibroblasts could be a novel therapeutic target in tumor therapy.
Human Influenza A Virus (IAV) Decreases Mitochondrial Respiration of Infected MDCK Cell
M Derakhshan,GEN Kass,MJ Carter
Iranian Journal of Public Health , 2005,
Abstract: Studies of interaction between viruses and mitochondria have shown that they can affect the mitochondria and induce mitochondrial alterations. Sometimes this interaction leads to induction or inhibition of apoptosis in infected cells. Interaction between adenoviruses and mitochondria showed the first evidence that a viral infection could affect the cell and induces apoptotic process. In addition, linkage between human diseases and mitochondrial dysfunction has been revealed. A Previously work showed that poliovirus infection led to decrease in total cellular respiration induced by inhibition of mitochondrial electron transport chain. We have screened different human viruses to observe their effect on mitochondrial respiration using Oxygen Electrode (OE). Here we report the effect of influenza A virus (IAV) on mitochondrial cell respiration. The addition of antimycin A (AA) to respiring cells completely blocked cellular respiration that indicates nearly all of the cellular consumption of oxygen is attributed to the mitochondria. Our result showed human influenza A virus (IAV) decreases total cell respiration in infected MDCK cells.
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