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Cun-Yu Wang

Publications and source records attributed to Cun-Yu Wang.

At least 19 recordsLinked to original sources
PubMed2007

A glycolytic mechanism regulating an angiogenic switch in prostate cancer.

The generation of an "angiogenic switch" is essential for tumor growth, yet its regulation is poorly understood. In this investigation, we explored the linkage between metastasis and angiogenesis through CXCL12/CXCR4 signaling. We found that CXCR4 regulates the expression and secretion of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1). Overexpression of PGK1 reduced the secretion of vascular endothelial growth factor and interleukin-8 and increased the generation of angiostatin. At metastatic sites, however, high levels of CXCL12 signaling through CXCR4 reduced PGK1 expression, releasing the angiogenic response for metastastic growth. These data suggest that PGK1 is a critical downstream target of the chemokine axis and an important regulator of an "angiogenic switch" that is essential for tumor and metastatic growth.

Angiostatins↗
PubMed2006

Mesenchymal stem cell-mediated functional tooth regeneration in swine.

Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla). Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs) to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.

Animals↗
PubMed2006

NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF.

Advanced breast cancers frequently metastasize to bone, resulting in osteolytic lesions, yet the underlying mechanisms are poorly understood. Here we report that nuclear factor-kappaB (NF-kappaB) plays a crucial role in the osteolytic bone metastasis of breast cancer by stimulating osteoclastogenesis. Using an in vivo bone metastasis model, we found that constitutive NF-kappaB activity in breast cancer cells is crucial for the bone resorption characteristic of osteolytic bone metastasis. We identified the gene encoding granulocyte macrophage-colony stimulating factor (GM-CSF) as a key target of NF-kappaB and found that it mediates osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Moreover, we observed that the expression of GM-CSF correlated with NF-kappaB activation in bone-metastatic tumor tissues from individuals with breast cancer. These results uncover a new and specific role of NF-kappaB in osteolytic bone metastasis through GM-CSF induction, suggesting that NF-kappaB is a potential target for the treatment of breast cancer and the prevention of skeletal metastasis.

Animals↗
PubMed2006

TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth.

Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.

AMP-Activated Protein Kinases↗
PubMed2006

Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa.

Cisplatin is one of the most common DNA-damaging agents used for treating patients with solid tumors such as squamous cell carcinoma (SCC). Unfortunately, significant levels of resistance in SCC cells emerge rapidly following cisplatin treatment. Here we report that the proteasome inhibitor PS-341, the representative of a new class of chemotherapeutic drugs, was capable of inducing apoptosis in cisplatin-resistant SCC cells via the endoplasmic reticulum stress. PS-341 stimulated the phosphorylation of PERK and the unfolded protein response, resulting in the induction of the transcription factor ATF-4. Importantly, the Bcl-2 homology domain 3-only (BH3-only) protein Noxa was found to be strongly induced in cisplatin-resistant SCC cells by PS-341 but not by cisplatin. The knock-down of Noxa using small interference RNA significantly abolished PS-341-mediated apoptosis in SCC cells. Using eIF2alpha mutant mouse embryonic fibroblasts, we found that functional eIF2alpha played an essential role in PS-341-induced Noxa expression. Taken together, our novel findings reveal a direct link between PS-341-induced endoplasmic reticulum stress and the mitochondria-dependent apoptotic pathway and suggest that PS-341 may be utilized for overcoming cisplatin-resistance in human SCC.

Animals↗
PubMed2006

A dominant function of IKK/NF-kappaB signaling in global lipopolysaccharide-induced gene expression.

Porphyromonas gingivalis is an etiologic pathogen of periodontitis that is one of the most common inflammatory diseases. Recently, we found that P. gingivalis LPS activated the transcription factor nuclear factor-kappaB (NF-kappaB) through the IkappaB kinase complex (IKK). NF-kappaB is a transcription factor that controls inflammation and host responses. In this study, we examined the role of IKK/NF-kappaBin P. gingivalis LPS-induced gene expression on a genome-wide basis using a combination of microarray and biochemical approaches. A total of 88 early response genes were found to be induced by P. gingivalis LPS in a human THP.1 monocytic cell lines. Interestingly, the induction of most of these genes was abolished or attenuated under the inactivation of IKK/NF-kappaB. Among those IKK/NF-kappaB-dependent genes, 20 genes were NF-kappaB-inducible genes reported previously, and 59 genes represented putative novel NF-kappaB target genes. Using transcription factor binding analysis, we found that most of these putative NF-kappaB target genes contained one or multiple NF-kappaB-binding sites. Also, some transcription factor-binding motifs were overrepresented in the promoter of both known and putative NF-kappaB-dependent genes, indicating that these genes may be regulated in a similar fashion. Furthermore, we found that several transcription factors associated with metabolic and inflammatory responses, including nuclear receptors, activator of protein-1, and early growth responses, were induced by P. gingivalis LPS through IKK/NF-kappaB, indicating that IKK/NF-kappaB may utilize these transcription factors to mediate secondary responses. Taken together, our results demonstrate that IKK/NF-kappaB signaling plays a dominant role in P. gingivalis LPS-induced early response gene expression, suggesting that IKK/NF-kappaB is a therapeutic target for periodontitis.

Animals↗
PubMed2006

Proteasome inhibitor induces apoptosis through induction of endoplasmic reticulum stress.

The 26S proteasome is a large multi-subunit protein complex found in the cytoplasm and nucleus of mammalian cells which plays a critical role in intracellular proteolysis. It has been found that the 26S proteasome degrades multiple important substrates which are associated with tumor growth and development. Emerging evidence demonstrates that proteasome inhibition is an innovative and effective approach for treating some human cancers. PS-341 (also known as Velcade or Bortezomib), a specific inhibitor of the 26S proteasome, has been approved for treating multiple myeloma by the FDA. PS-341 mainly exhibits its anti-cancer effect by inducing apoptosis, and has been found to affect several pro- and anti-apoptotic pathways. Activation of the transcription factor nuclear factor kappa B (NF-kappaB), a key survival factor, is dependent on the 26S proteasome. The inhibition of NF-kappaB by PS-341 has been found to induce apoptosis in several human cancer cells and is considered to be one of the primary targets of the PS-341 anti-tumor effect. More recently, studies have suggested that, in addition to the inhibition of pro-survivial NF-kappaB, PS-341 may induce apoptosis by stimulating pro-apoptotic endoplasmic reticulum stress through proteasome inhibition. In this review, we will mainly discuss recent progress on the elucidation of the molecular mechanism of PS-341-mediated apoptosis.

Apoptosis↗
PubMed2006

Notch signaling in the regulation of tumor angiogenesis.

The Notch signaling pathway is conserved in vertebrates and invertebrates and is involved in many developmental processes. Notch receptors and ligands are expressed on the cell surface enabling interactions between adjacent cells upon receptor-ligand binding. Notch signaling molecules have an important well-documented role in vascular development, differentiation, proliferation, apoptosis and tumorigenesis. Recently, several groups have identified the importance of Notch signaling in tumor angiogenesis. Notch activity increases specifically in tumor endothelium and in various tumors types and, in some studies, Notch signaling suppresses angiogenic processes. Because the Notch signaling pathway can mediate communication between various cell types in the tumor microenvironment, interactions between tumor cells and endothelial cells might promote angiogenesis, therefore targeting the Notch pathway might provide a novel strategy for anti-angiogenic therapies. Here, we discuss recent insights of Notch signaling in tumor angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2006

IKKalpha stabilizes cytosolic beta-catenin by inhibiting both canonical and non-canonical degradation pathways.

Beta-catenin is a bi-functional protein. It is not only a major component of the cellular adhesion machinery, but is also a transcription co-activator of the Wnt signaling pathway. The cytosolic levels of the beta-catenin protein, as well as its subcellular localization, are tightly regulated due to its oncogenic potentials. Two independent pathways are found to regulate beta-catenin. The canonical pathway is induced by the Axin/adenomatous polyposis coli (APC)/glycogen synthase kinase-3beta (GSK-3beta) complex which is dependent on GSK-3beta phosphorylation. The non-canonical pathway is mediated by p53-induced Siah-1 which is GSK-3beta phosphorylation-independent. Recently, several studies reported that IkappaB kinase alpha (IKKalpha) could stabilize beta-catenin and stimulate beta-catenin/T cell factor (Tcf)-dependent transcription. Here we report that IKKalpha could inhibit beta-catenin degradation mediated not only by the Axin/APC/GSK-3beta complex, but also by the Siah-1 pathway. Consistently, we found that IKKalpha abolished the inhibition of beta-catenin/Tcf-dependent transcription by Siah-1. Furthermore, we found that IKKalpha interacted with beta-catenin and inhibited beta-catenin ubiquitination. Taken together, our results provide a new insight into IKKalpha-mediated beta-catenin stabilization.

Animals↗
PubMed2005

Clusterin inhibits apoptosis by interacting with activated Bax.

Clusterin is an enigmatic glycoprotein that is overexpressed in several human cancers such as prostate and breast cancers, and squamous cell carcinoma. Because the suppression of clusterin expression renders human cancer cells sensitive to chemotherapeutic drug-mediated apoptosis, it is currently an antisense target in clinical trials for prostate cancer. However, the molecular mechanisms by which clusterin inhibits apoptosis in human cancer cells are unknown. Here we report that intracellular clusterin inhibits apoptosis by interfering with Bax activation in mitochondria. Intriguingly, in contrast to other inhibitors of Bax, clusterin specifically interacts with conformation-altered Bax in response to chemotherapeutic drugs. This interaction impedes Bax oligomerization, which leads to the release of cytochrome c from mitochondria and caspase activation. Moreover, we also find that clusterin inhibits oncogenic c-Myc-mediated apoptosis by interacting with conformation-altered Bax. Clusterin promotes c-Myc-mediated transformation in vitro and tumour progression in vivo. Taken together, our results suggest that the elevated level of clusterin in human cancers may promote oncogenic transformation and tumour progression by interfering with Bax pro-apoptotic activities.

Animals↗
PubMed2005

Wnt/beta-catenin signaling inhibits death receptor-mediated apoptosis and promotes invasive growth of HNSCC.

The Wnt/beta-catenin signaling pathway plays a critical role in cell proliferation and oncogenesis. It has been found to be chronically activated in a variety of human cancers, including head and neck squamous cell carcinoma (HNSCC). Previously, we have found that the activation of the Wnt/beta-catenin signaling pathway inhibits mitochondria-mediated apoptosis. In this study, we extended our studies to determine whether the Wnt/beta-catenin signaling pathway inhibited death receptor-mediated apoptosis in HNSCC cells. We found that Wnt/beta-catenin inhibited not only tumor necrosis factor (TNF)/c-Myc-mediated apoptosis, but also cell detachment-mediated apoptosis (anoikis) which is dependent on the death receptor signaling pathway. Interestingly, we also observed that the Wnt/beta-catenin signaling pathway induced HNSCC cell scattering and promoted cell invasion in the Matrigel, both of which are hallmarks for the invasive growth of HNSCC. Consistently, the over-expression of beta-catenin promoted HNSCC tumor growth in nude mice. Taken together, our results suggest that the Wnt/beta-catenin signaling pathway plays dual functions in HNSCC development: promoting both cell survival and invasive growth of HNSCC cells.

Animals↗
PubMed2005

Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines.

Vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in tumor-associated microvascular endothelial cells. We have previously reported that up-regulated Bcl-2 expression in microvascular endothelial cells is sufficient to enhance intratumoral angiogenesis and to accelerate tumor growth. We initially attributed these results to Bcl-2-mediated endothelial cell survival. However, in recent experiments, we observed that conditioned medium from Bcl-2-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-2) is sufficient to induce potent neovascularization in the rat corneal assay, whereas conditioned medium from empty vector controls (HDMEC-LXSN) does not induce angiogenesis. These results cannot be attributed to the role of Bcl-2 in cell survival. To understand this unexpected observation, we did gene expression arrays that revealed that the expression of the proangiogenic chemokines interleukin-8 (CXCL8) and growth-related oncogene-alpha (CXCL1) is significantly higher in HDMEC exposed to VEGF and in HDMEC-Bcl-2 than in controls. Inhibition of Bcl-2 expression with small interfering RNA-Bcl-2, or the inhibition of Bcl-2 function with small molecule inhibitor BL-193, down-regulated CXCL8 and CXCL1 expression and caused marked decrease in the angiogenic potential of endothelial cells without affecting cell viability. Nuclear factor-kappaB (NF-kappaB) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-kappaB down-regulated CXCL8 and CXCL1 expression levels. These results reveal a novel function for Bcl-2 as a proangiogenic signaling molecule and suggest a role for this pathway in tumor angiogenesis.

Animals↗
PubMed2005

Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling.

While significant progress has been made in understanding the induction of tumor vasculature by secreted angiogenic factors, little is known regarding contact-dependent signals that promote tumor angiogenesis. Here, we report that the Notch ligand Jagged1 induced by growth factors via mitogen-activating protein kinase (MAPK) in head and neck squamous cell carcinoma (HNSCC) cells triggered Notch activation in neighboring endothelial cells (ECs) and promoted capillary-like sprout formation. Jagged1-expressing HNSCC cells significantly enhanced neovascularization and tumor growth in vivo. Moreover, the level of Jagged1 was significantly correlated with tumor blood vessel content and associated with HNSCC development. Our results elucidate a novel mechanism by which the direct interplay between tumor cells and ECs promotes angiogenesis through MAPK and Notch signaling pathways.

Animals↗
PubMed2004

Monomethyl branched-chain fatty acids play an essential role in Caenorhabditis elegans development.

Monomethyl branched-chain fatty acids (mmBCFAs) are commonly found in many organisms from bacteria to mammals. In humans, they have been detected in skin, brain, blood, and cancer cells. Despite a broad distribution, mmBCFAs remain exotic in eukaryotes, where their origin and physiological roles are not understood. Here we report our study of the function and regulation of mmBCFAs in Caenorhabditis elegans, combining genetics, gas chromatography, and DNA microarray analysis. We show that C. elegans synthesizes mmBCFAs de novo and utilizes the long-chain fatty acid elongation enzymes ELO-5 and ELO-6 to produce two mmBCFAs, C15ISO and C17ISO. These mmBCFAs are essential for C. elegans growth and development, as suppression of their biosynthesis results in a growth arrest at the first larval stage. The arrest is reversible and can be overcome by feeding the arrested animals with mmBCFA supplements. We show not only that the levels of C15ISO and C17ISO affect the expression of several genes, but also that the activities of some of these genes affect biosynthesis of mmBCFAs, suggesting a potential feedback regulation. One of the genes, lpd-1, encodes a homolog of a mammalian sterol regulatory element-binding protein (SREBP 1c). We present results suggesting that elo-5 and elo-6 may be transcriptional targets of LPD-1. This study exposes unexpected and crucial physiological functions of C15ISO and C17ISO in C. elegans and suggests a potentially important role for mmBCFAs in other eukaryotes.

Acetyltransferases↗
PubMed2004

The zinc finger mutation C417R of I-kappa B kinase gamma impairs lipopolysaccharide- and TNF-mediated NF-kappa B activation through inhibiting phosphorylation of the I-kappa B kinase beta activation loop.

The activation of the I-kappaB kinase (IKK) complex by TNF or LPS stimulates phosphorylation and degradation of I-kappaBalpha, leading to the nuclear translocation of NF-kappaB. The IKK complex is mainly composed of two catalytic subunits, IKKalpha and IKKbeta, and a chaperon subunit IKKgamma. Although IKKgamma does not have catalytic activity, it is essential for IKK activation induced by multiple stimuli. Importantly, the key residue cysteine 417 at the zinc finger domain of IKKgamma has been found to be mutated to arginine (IKKgammaC417R) in a human genetic disorder called the anhydrotic ectodermal dysplasia with immunodeficiency. To understand the underlying mechanisms of immunodeficiency, we examined whether the IKKgammaC417R mutant modified IKK activation and NF-kappaB transcription stimulated by LPS or TNF in human monocytes. We found that overexpression of IKKgammaC417R severely impaired LPS- and TNF-induced I-kappaBalpha phosphorylation and degradation in a dominant-negative fashion. Also, LPS- and TNF-induced NF-kappaB transcription was inhibited by IKKgammaC417R. The reconstitution of IKKgamma, but not IKKgammaC417R, in IKKgamma-deficient cells restored NF-kappaB signaling, indicating the zinc finger structure of IKKgamma plays a key role in IKK activation. Moreover, C417R mutation in IKKgamma abolished both LPS- and TNF-induced phosphorylation of the activation loop of IKKbeta. Collectively, our results indicated that the zinc finger structure of IKKgamma plays a key role in LPS- and TNF-induced NF-kappaB activation. The anhydrotic ectodermal dysplasia with immunodeficiency patients' immunodeficiency may be associated with NF-kappaB defect in response to bacterial stimulation.

Active Transport, Cell Nucleus↗
PubMed2004

Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells.

PS-341, also known as Velcade or Bortezomib, represents a new class of anticancer drugs which has been shown to potently inhibit the growth and/or progression of human cancers, including head and neck squamous cell carcinoma (HNSCC). Although it has been logically hypothesized that NF-kappaB is a major target of PS-341, the underlying mechanism by which PS-341 inhibits tumor cell growth is unclear. Here we found that PS-341 potently activated the caspase cascade and induced apoptosis in human HNSCC cell lines. Although PS-341 could inhibit NF-kappaB activation, the inhibition of NF-kappaB was not sufficient to initiate apoptosis in HNSCC cells. Using biochemical and microarray approaches, we found that proteasome inhibition by PS-341 induced endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in HNSCC cells. The inhibition of ROS significantly suppressed caspase activation and apoptosis induced by PS-341. Consistently, PS-341 could not induce the ER stress-ROS in PS-341-resistant HNSCC cells. Taken together, our results suggest that in addition to the abolishment of the prosurvival NF-kappaB, PS-341 might directly induce apoptosis by activating proapoptotic ER stress-ROS signaling cascades in HNSCC cells, providing novel insights into the PS-341-mediated antitumor activity.

Antineoplastic Agents↗