Inhibition of tumour angiogenesis has an important role in antitumour therapy. However, a recent study indicates that antiangiogenesis therapy may lead to glucose-related protein 78 (GRP78) associated antiapoptotic resistance. The present study aims to elucidate the dual effects of plasminogen kringle 5 (K5) on tumour angiogenesis and apoptosis induction by targeting hypoxia-inducible factor 1α (HIF-1α) and GRP78. Co-immunoprecipitation and western blotting were used for examining the ubiquitination of HIF-1α and analysing angiogenesis and apoptosis-associated proteins. K5 promoted the sumo/ubiquitin-mediated proteasomal degradation of HIF-1α by upregulating von Hippel-Lindau protein under hypoxia, resulting in the reduction of vascular endothelial growth factor and thus suppressing tumour angiogenesis. Furthermore, K5 decreased GRP78 expression via downregulation of phosphorylated extracellular-regulated protein kinase, leading to caspase-7 cleavage and tumour cell apoptosis. Blocking voltage-dependent anion channel abrogated the effects of K5 on both HIF-1α and GRP78. K5 significantly inhibited the growth of gastric carcinoma xenografts by inhibiting both angiogenesis and apoptosis. The dual effects suggest that K5 might be a promising bio-therapeutic agent in the treatment of gastric cancer, particularly in patients who exhibit the induction of GRP78.
Last. Ahmedin Jemal(ACS: American Cancer Society)H-Index: 139
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Abstract Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Can...
Last. Guo Quan Gao(SYSU: Sun Yat-sen University)H-Index: 4
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Human plasminogen kringle 5 (K5) is known to display its potent anti-angiogenesis effect through inducing endothelial cell (EC) apoptosis, and the voltage-dependent anion channel 1 (VDAC1) has been identified as a receptor of K5. However, the exact role and underlying mechanisms of VDAC1 in K5-induced EC apoptosis remain elusive. In the current study, we showed that K5 increased the protein level of VDAC1, which initiated the mitochondrial apoptosis pathway of ECs. Our findings also showed that ...
#1Manish A. Shah(NewYork–Presbyterian Hospital)H-Index: 72
The international phase III REGARD study demonstrated improved overall survival with ramucirumab as second-line therapy for patients with advanced-stage gastric and gastroesophageal junction adenocarcinoma. As a novel biological treatment, is ramucirumab also the harbinger of a new era of targeted therapies in this prevalent and highly morbid disease?
Rationale: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. Objective: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. Methods and Results: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arterie...
#1Wei Bin Cai(SYSU: Sun Yat-sen University)H-Index: 3
#2Yang Zhang(SYSU: Sun Yat-sen University)H-Index: 23
Last. Guo Quan Gao(SYSU: Sun Yat-sen University)H-Index: 4
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We had demonstrated that plasminogen kringle 5 (K5), a potent angiogenic inhibitor, inhibited retinal neovascularization and hepatocellular carcinoma growth by anti-angiogenesis. The current study investigated the effects and the underlying mechanisms of K5 on both tumor growth and spontaneous pulmonary metastasis in Lewis lung carcinoma (LLC) implanted mouse model. Similarly, K5 could decrease expression of VEGF in LLC cells and grafted tissues and suppress tumor angiogenesis and growth. K5 had...
Last. De Yun Wang(NUS: National University of Singapore)H-Index: 42
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Background Nasal polyposis (NP) is a Th2-skewed inflammatory disorder, but it is unclear what role regulatory T cells (T-reg) play in disease pathology. We investigated the expression profiles of T-reg and T-helper-cell-associated genes and their response to glucocorticosteroid (GC) treatment in Chinese patients with NP. Methods Biopsies were obtained from 29 non-treated NP patients for comparison with inferior turbinates collected from healthy controls. In 13 patients, NP samples were collected...
Etiological concepts on cancer development, malignant growth and tumour propagation have undergone a revolutionary development during recent years: Among other aspects, the discovery of angiogenesis – the growth of new blood vessels from pre-existing vasculature – as a key element in the pathogenesis of malignancy has opened an abundance of biologic insights and subsequent therapeutic options, which have led to improved prognosis in many cancers including those originating from colon, lung, brea...
#2Danya Ben-Hail(BGU: Ben-Gurion University of the Negev)H-Index: 14
Abstract Regulation of mitochondrial physiology requires an efficient exchange of molecules between mitochondria and the cytoplasm via the outer mitochondrial membrane (OMM). The voltage-dependent anion channel (VDAC) lies in the OMM and forms a common pathway for the exchange of metabolites between the mitochondria and the cytosol, thus playing a crucial role in the regulation of metabolic and energetic functions of mitochondria. VDAC is also recognized to function in mitochondria-mediated apop...
#1Ruiqing Wang(City of Hope National Medical Center)H-Index: 9
#2Huimin Xie(UIC: University of Illinois at Chicago)H-Index: 8
Last. Zuoming Sun(City of Hope National Medical Center)H-Index: 26
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Survival of CD4 + CD8 + double-positive (DP) thymocytes plays a critical role in shaping the peripheral T cell repertoire. However, the mechanisms responsible for the regulation of DP thymocyte lifespan remain poorly understood. In this work, we demonstrate that T cell factor (TCF)-1 regulates DP thymocyte survival by upregulating RORγt. Microarray analysis revealed that RORγt was significantly downregulated in TCF-1 −/− thymocytes that underwent accelerated apoptosis, whereas RORγt was greatly ...
#2Jerry E. Stewart(UAB: University of Alabama at Birmingham)H-Index: 18
Last. Candece L. Gladson(UAB: University of Alabama at Birmingham)H-Index: 47
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Recombinant plasminogen kringle 5 (rK5) has been shown to induce apoptosis of dermal microvessel endothelial cells (MvEC) in a manner that requires glucose-regulated protein 78 (GRP78). As we are interested in anti-angiogenic therapy for glioblastoma tumors, and the effectiveness of anti-angiogenic therapy can be enhanced when combined with radiation, we investigated the pro-apoptotic effects of rK5 combined with radiation on brain MvEC. We found that rK5 treatment of brain MvEC induced apoptosi...
#1Thomas Neill(Thomas Jefferson University)H-Index: 30
#2Aastha Kapoor(Thomas Jefferson University)H-Index: 8
Last. Renato V. Iozzo(Thomas Jefferson University)H-Index: 126
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Proteoglycans and selected extracellular matrix constituents are emerging as intrinsic and critical regulators of evolutionarily conversed, intracellular catabolic pathways. Often, these secreted molecules evoke sustained autophagy in a variety of cell types, tissues, and model systems. The unique properties of proteoglycans have ushered in a paradigmatic shift to broaden our understanding of matrix-mediated signaling cascades. The dynamic cellular pathway controlling autophagy is now linked to ...
Gastric cancer (GC) is still ranked fourth among malignant cancers and remained as the second leading cause of cancer related death. There is mounting evidence that emphasizes on the need for further investigation on the specific receptors overexpression roles in GC progression. Low efficiency and impotence of the common methods for targeting gastric tumorigenesis and related metastases are enough to convince researchers to continue their investigation on new approaches of effective GC targeting...
Fibrinolytic factors like plasminogen, tissue-type plasminogen activator (tPA), and urokinase plasminogen activator (uPA) dissolve clots. Though mere extracellular-matrix-degrading enzymes, fibrinolytic factors interfere with many processes during primary cancer growth and metastasis. Their many receptors give them access to cellular functions that tumor cells have widely exploited to promote tumor cell survival, growth, and metastatic abilities. They give cancer cells tools to ensure their own ...
Gastric carcinoma is a common malignant cancer. Pyruvate kinase M2 (PKM2) is highly expressed in cancers, including gastric carcinoma. However, its function and molecular mechanism in gastric carcinoma remains unclear. Here, we aimed to explore the function and the underlying mechanism of PKM2 on malignant phenotypes in gastric carcinoma. In this study, the mRNA levels and protein levels of PKM2 in gastric carcinoma cell lines and normal gastric mucosa epithelial cell lines were detected using q...
#1Jin-Yun Li(CSU: Central South University)H-Index: 2
#2Wenxiao Huang(CSU: Central South University)H-Index: 3
Last. Yaoyun Tang(CSU: Central South University)H-Index: 3
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Objective:To construct plasmids with Hre2.Grp78 chimeric promoter regulating fusion gene TK/VP3 and elaborate the effects of overexpressed TK/VP3 on nasopharyngeal carcinoma cells.Methods:Four plas...
#1Ruowen Ge(NUS: National University of Singapore)H-Index: 32
#2Chieh Kao(NUS: National University of Singapore)H-Index: 3
Cell surface GRP78 (csGRP78, glucose-regulated protein 78 kDa) is preferentially overexpressed in aggressive, metastatic, and chemo-resistant cancers. GRP78 is best studied as a chaperone protein in the lumen of endoplasmic reticulum (ER), facilitating folding and secretion of the newly synthesized proteins and regulating protein degradation as an ER stress sensor in the unfolded protein pathway. As a cell surface signal receptor, multiple csGRP78 ligands have been discovered to date, and they t...