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Search Results: 1 - 10 of 18240 matches for " Bingliang Fang "
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Apoptosis Induction by MEK Inhibition in Human Lung Cancer Cells Is Mediated by Bim
Jieru Meng,Bingliang Fang,Yong Liao,Christine M. Chresta,Paul D. Smith,Jack A. Roth
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013026
Abstract: AZD6244 (ARRY-142886) is an inhibitor of MEK1/2 and can inhibit cell proliferation or induce apoptosis in a cell-type dependent manner. The precise molecular mechanism of AZD6244-induced apoptosis is not clear. To investigate mechanisms of AZD6244 induced apoptosis in human lung cancer, we determined the molecular changes of two subgroups of human lung cancer cell lines that are either sensitive or resistant to AZD6244 treatment. We found that AZD6244 elicited a large increase of Bim proteins and a smaller increase of PUMA and NOXA proteins, and induced cell death in sensitive lung cancer cell lines, but had no effect on other Bcl-2 related proteins in those cell lines. Knockdown of Bim by siRNA greatly increased the IC50 and reduced apoptosis for AZD6244 treated cells. We also found that levels of endogenous p-Thr32-FOXO3a and p-Ser253-FOXO3a were lower in AZD6244-sensitive cells than in AZD6244-resistant cells. In the sensitive cells, AZD6244 induced FOXO3a nuclear translocation required for Bim activation. Moreover, the silencing of FOXO3a by siRNA abrogated AZD6244-induced cell apoptosis. In addition, we found that transfection of constitutively active AKT up-regulated p-Thr32-FOXO3a and p-Ser253-FOXO3a expression and inhibited AZD6244-induced Bim expression in sensitive cells. These results show that Bim plays an important role in AZD6244-induced apoptosis in lung cancer cells and that the PI3K/AKT/FOXO3a pathway is involved in Bim regulation and susceptibility of lung cancer cells to AZD6244. These results have implications in the development of strategies to overcome resistance to MEK inhibitors.
Oxidative stress in NSC-741909-induced apoptosis of cancer cells
Xiaoli Wei, Wei Guo, Shuhong Wu, Li Wang, Peng Huang, Jinsong Liu, Bingliang Fang
Journal of Translational Medicine , 2010, DOI: 10.1186/1479-5876-8-37
Abstract: The generation of ROS was measured by using the cell-permeable nonfluorescent compound H2DCF-DA and flow cytometry analysis. Cell viability was determined by sulforhodamine B assay. Western blot analysis, immunofluorescent staining and flow cytometry assays were used to determine apoptosis and molecular changes induced by NSC-741909.Treatment with NSC-741909 induced robust ROS generation and marked MAPK phosphatase-1 and -7 clustering in NSC-741909-sensitive, but not resistant cell lines, in a dose- and time-dependent manner. The generation of ROS was detectable as early as 30 min and ROS levels were as high as 6- to 8-fold above basal levels after treatment. Moreover, the NSC-741909-induced ROS generation could be blocked by pretreatment with antioxidants, such as nordihydroguaiaretic acid, aesculetin, baicalein, and caffeic acid, which in turn, inhibited the NSC-741909-induced JNK activation and apoptosis.Our results demonstrate that the increased ROS production was associated with NSC-741909-induced antitumor activity and that ROS generation and subsequent JNK activation is one of the primary mechanisms of NSC-741909-mediated antitumor cell activity.We recently identified a small molecule (oncrasin-1) through cell-based synthetic lethality screening that can effectively kill several lung cancer cell lines harboring mutant K-Ras genes [1]. Subsequent analyses of oncrasin-1 analogues led us to identify several active compounds with similar chemical structures. NSC-741909 is one of the oncrasin-1 analogues that was highly active against several cell lines derived from lung, colon, breast, ovarian, and kidney cancers when tested in NCI-60 cancer cell lines by the Developmental Therapeutics Program at the National Cancer Institute. Using a reverse-phase protein microarray assay, we determined molecular changes in 77 protein biomarkers in an oncrasin-sensitive lung cancer cell line after treatment with NSC-741909 [2]. These results showed that treatment with NSC-741909
Antitumor Activity of a Novel Oncrasin Analogue Is Mediated by JNK Activation and STAT3 Inhibition
Wei Guo,Shuhong Wu,Li Wang,Xiaoli Wei,Xiaoying Liu,Ji Wang,Zhimin Lu,Melinda Hollingshead,Bingliang Fang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0028487
Abstract: To optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3-methanol, oncrasin-72), one of most potent analogues of oncrasin-1.
The Tumor Suppressor Gene TUSC2 (FUS1) Sensitizes NSCLC to the AKT Inhibitor MK2206 in LKB1-dependent Manner
Jieru Meng, Mourad Majidi, Bingliang Fang, Lin Ji, B. Nebiyou Bekele, John D. Minna, Jack A. Roth
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077067
Abstract: TUSC2-defective gene expression is detected in the majority of lung cancers and is associated with worse overall survival. We analyzed the effects of TUSC2 re-expression on tumor cell sensitivity to the AKT inhibitor, MK2206, and explored their mutual signaling connections, in vitro and in vivo. TUSC2 transient expression in three LKB1-defective non-small cell lung cancer (NSCLC) cell lines combined with MK2206 treatment resulted in increased repression of cell viability and colony formation, and increased apoptotic activity. In contrast, TUSC2 did not affect the response to MK2206 treatment for two LKB1-wild type NSCLC cell lines. In vivo, TUSC2 systemic delivery, by nanoparticle gene transfer, combined with MK2206 treatment markedly inhibited growth of tumors in a human LKB1-defective H322 lung cancer xenograft mouse model. Biochemical analysis showed that TUSC2 transient expression in LKB1-defective NSCLC cells significantly stimulated AMP-activated protein kinase (AMPK) phosphorylation and enzymatic activity. More importantly, AMPK gene knockdown abrogated TUSC2-MK2206 cooperation, as evidenced by reduced sensitivity to the combined treatment. Together, TUSC2 re-expression and MK2206 treatment was more effective in inhibiting the phosphorylation and kinase activities of AKT and mTOR proteins than either single agent alone. In conclusion, these findings support the hypothesis that TUSC2 expression status is a biological variable that potentiates MK2206 sensitivity in LKB1-defective NSCLC cells, and identifies the AMPK/AKT/mTOR signaling axis as an important regulator of this activity.
Pathophysiological Significance of Hepatic Apoptosis
Kewei Wang,Bingliang Lin
ISRN Hepatology , 2013, DOI: 10.1155/2013/740149
Abstract: Apoptosis is a classical pathological feature in liver diseases caused by various etiological factors such as drugs, viruses, alcohol, and cholestasis. Hepatic apoptosis and its deleterious effects exacerbate liver function as well as involvement in fibrosis/cirrhosis and carcinogenesis. An imbalance between apoptotic and antiapoptotic capabilities is a prominent characteristic of liver injury. The regulation of apoptosis and antiapoptosis can be a pivotal step in the treatment of liver diseases. 1. Apoptosis Apoptosis is a process of programmed cell death. Apoptotic cells are characterized by energy-dependent biochemical mechanisms and obvious morphological changes [1, 2]. These features include membrane blebbing, cell shrinkage, nuclear chromatin condensation, and chromosomal DNA fragmentation. The apoptotic process deletes single cell or small clusters of cells without inflammatory response [3]. Apoptotic cells die in a controlled and regulated fashion. This makes apoptosis distinct from other uncontrolled modes of cell death such as necrosis, necroptosis, autophagy, and cornification [4]. Uncontrolled cell death leads to cell lysis, inflammatory response, and serious health problems [5]. Apoptosis is associated with multiple pathophysiological functions. During the embryological stage of mammals, apoptosis is important for the normal development of organs [6]. In adults, apoptosis regulates physiological processes (e.g., removing aged cells) and maintains tissue homeostasis [7]. Dysfunction or dysregulation of the apoptotic program is implicated in a variety of congenital anomalies and pathological conditions such as tumorigenesis, autoimmune diseases, neurodegenerative disorders, and others [8]. 2. Hepatic Apoptosis Hepatic apoptosis, as name indicated, means cell suicide in liver. The hepatic apoptosis is different from hepatocyte apoptosis. The hepatocyte apoptosis describes the apoptotic cell death in only hepatocytes (one type of liver cells), but the hepatic apoptosis reflects the interaction of manifold cells in liver and represents a comprehensive outcome of multiple effects. The liver is an organ consisting of several phenotypically distinct cell types, for example, hepatocytes, cholangiocytes, stellate cells, sinusoidal endothelial cells, Kupffer cells, oval cells, and so forth [9]. Predominant hepatocytes make up 70–80% of the liver cells [10]. Hepatocytes manufacture critical circulating proteins, generate bile acid-dependent bile flow, detoxify endo- and xenobiotics, and regulate intermediary metabolism [11]. Hepatocyte injury results
Elafin, an inhibitor of elastase, is a prognostic indicator in breast cancer
Kelly K Hunt, Hannah Wingate, Tomoya Yokota, Yanna Liu, Gordon B Mills, Fan Zhang, Bingliang Fang, Chun-Hui Su, Ming Zhang, Min Yi, Khandan Keyomarsi
Breast Cancer Research , 2013, DOI: 10.1186/bcr3374
Abstract: Panels of normal and immortalized breast epithelial cells, along with breast carcinoma cells, were used to examine the impact of adenoviral-mediated elafin expression or shRNA-mediated inhibition of elastase on the growth of cells and xenografts in nude mice. To determine the prognostic significance of decreased elafin in patients with invasive breast cancer, previously published gene array datasets were interrogated.Elafin expression had no effect on non-tumorigenic cells but resulted in marked inhibition of cell growth in breast cancer cell lines. Control-treated xenografts generated a tumor burden that necessitated sacrifice within one month of initial treatment, whereas xenograft-bearing mice treated with Ad-Elafin were alive at eight months with marked reduction in tumor growth. Elastase inhibition mimicked these results, showing decreased tumor cell growth in vitro and in vivo. Low expression of elafin gene correlated with significantly reduced time to relapse, and when combined with high expression of elastase gene was associated with decreased survival in breast cancer patients.Our data suggest that elafin plays a direct role in the suppression of tumors through inhibition of elastase and thus serves as a prognostic indicator for breast cancer patients.Polymorphonuclear leukocyte elastase (hereafter referred to as elastase) disintegrates matrix proteins [1], implicating this enzyme in breast cancer cell invasion and metastasis. Elastase is produced by neutrophils and also by human breast cancer cells but not by normal breast epithelial cells in culture [2]. Increased levels of elastase have been shown to be strongly associated with recurrence and death in breast cancer patients [3]. A study of 313 breast cancer patients with a median of 18.5 years of follow-up showed that elastase in tumor extracts was an independent prognostic factor associated with increased risk of recurrence [4]. These studies suggest that elastase could have a role in tumor progression
Targeting different types of human meningioma and glioma cells using a novel adenoviral vector expressing GFP-TRAIL fusion protein from hTERT promoter
Jessica T Li, Ka Bian, Alan L Zhang, Dong H Kim, William W Ashley, Rahul Nath, Ian McCutcheon, Bingliang Fang, Ferid Murad
Cancer Cell International , 2011, DOI: 10.1186/1475-2867-11-35
Abstract: Gliomas and meningiomas are the two most common types of human brain tumors. Currently there is no effective cure for recurrent malignant meningiomas or for gliomas. Ad/gTRAIL has been shown to be effective in killing selected lung, colon and breast cancer cells, but there have been no studies reporting its antitumor effects on malignant meningiomas. Therefore, we tested the antitumor effect of Ad/gTRAIL for the first time in human malignant meningioma and glioma cell lines, and in intracranial M6 and U87 xenografts.Materials and Methods: Human malignant meningioma and glioma cells were infected with adenoviruses, Ad/gTRAIL and Ad/CMV-GFP. Cell viability was determined by proliferation assay. FACS analysis and quantification of TRAIL were used to measure apoptosis in these cells. We injected Ad/gTRAIL viruses in intracranial M6 and U87 xenografts, and measured the brain tumor volume, quantified apoptosis by TUNEL assay in the brain tumor tissue.Our studies demonstrate that in vitro/in vivo treatment with Ad/gTRAIL virus resulted in significant increase of TRAIL activity, and elicited a greater tumor cell apoptosis in malignant brain tumor cells as compared to treatment with the control, Ad/CMV-GFP virus without TRAIL activity.We showed for the first time that adenovirus Ad/gTRAIL had significant antitumor effects against high grade malignant meningiomas as well as gliomas. Although more work needs to be done, our data suggests that Ad/gTRAIL has the potential to be useful as a tool against malignant brain tumors.Gliomas and meningiomas are the two most common types of human brain tumors. Malignant gliomas are the most aggressive and deadliest type of brain tumor[1]. Meningiomas, on the other hand, are usually benign but often recur after surgical removal. They can undergo malignant transformation, and depending on their location can be serious and even potentially lethal to patients [2]. It has been reported that there has been a steady increase in the incidence of
Downregulation of IFNG in CD4+ T Cells in Lung Cancer through Hypermethylation: A Possible Mechanism of Tumor-Induced Immunosuppression
Fang Wang, Jian Xu, Quan Zhu, Xuejun Qin, Yan Cao, Jiangfang Lou, Yuqiao Xu, Xing Ke, Qing Li, Erfu Xie, Lixia Zhang, Ruihong Sun, Liang Chen, Bingliang Fang, Shiyang Pan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079064
Abstract: Tumor survival is significantly correlated with the immune response of patients. IFNG plays an important role in the tumor host response and decreased IFNG expression is often observed in lung cancer. Studies have shown that CpG island hypermethylation plays a critical role in transcriptional silencing of IFNG gene expression. However, there is limited understanding regarding the molecular mechanisms of altered methylation, and whether the tumor microenvironment has any effect on DNA methylation and IFNG production. In the current study, we demonstrate that plasma and intra-cellular IFNG levels are significantly lower in lung cancer patients. Hypermethylation of the IFNG promoter in CD4+ T cells and plasma IFNG was negatively correlated. CD4+ T cells from healthy individuals co-cultured with SPC-A1 cells generated lower levels of IFNG after activation, elevated expression of DNA methyltransferases (DNMTs), and exhibited hypermethylation of the IFNG promoter. In conclusion, decreased IFNG expression of CD4+ T cells co-cultured with lung cancer cell is associated with IFNG promoter hypermethylation. Our study suggests that interaction between lung cancer cells and CD4+ T cells induces DNMT expression and IFNG promoter hypermethylation in CD4+ T cell, which may serve as an important mechanism of tumor-induced immunosuppression.
The Role of PKR/eIF2α Signaling Pathway in Prognosis of Non-Small Cell Lung Cancer
Yong He, Arlene M. Correa, Maria Gabriela Raso, Wayne L. Hofstetter, Bingliang Fang, Carmen Behrens, Jack A. Roth, Yihong Zhou, Liping Yu, Ignacio I. Wistuba, Stephen G. Swisher, Apar Pataer
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024855
Abstract: Background In this study, we investigated whether PKR protein expression is correlated with mRNA levels and also evaluated molecular biomarkers that are associated with PKR, such as phosphorylated PKR (p-PKR) and phosphorylated eIF2α (p-eIF2α). Methodology and Findings We determined the levels of PKR protein expression and mRNA in 36 fresh primary lung tumor tissues by using Western blot analysis and real-time reverse-transcriptase PCR (RT-PCR), respectively. We used tissue microarrays for immunohistochemical evaluation of the expression of p-PKR and p-eIF2α proteins. We demonstrated that PKR mRNA levels are significantly correlated with PKR protein levels (Spearman's rho = 0.55, p<0.001), suggesting that PKR protein levels in tumor samples are regulated by PKR mRNA. We also observed that the patients with high p-PKR or p-eIF2α expression had a significantly longer median survival than those with little or no p-PKR or p-eIF2α expression (p = 0.03 and p = 0.032, respectively). We further evaluated the prognostic effect of combined expression of p-PKR plus PKR and p-eIF2α plus PKR and found that both combinations were strong independent prognostic markers for overall patient survival on stage I and all stage patients. Conclusions Our findings suggest that PKR protein expression may controlled by transcription level. Combined expression levels of PKR and p-PKR or p-eIF2α can be new markers for predicting the prognosis of patients with NSCLC.
Combination Treatment with MEK and AKT Inhibitors Is More Effective than Each Drug Alone in Human Non-Small Cell Lung Cancer In Vitro and In Vivo
Jieru Meng,Bingbing Dai,Bingliang Fang,B. Nebiyou Bekele,William G. Bornmann,Duoli Sun,Zhenghong Peng,Roy S. Herbst,Vassiliki Papadimitrakopoulou,John D. Minna,Michael Peyton,Jack A. Roth
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014124
Abstract: AZD6244 and MK2206 are targeted small-molecule drugs that inhibit MEK and AKT respectively. The efficacy of this combination in lung cancer is unknown. Our previous work showed the importance of activated AKT in mediating resistance of non-small cell lung cancer (NSCLC) to AZD6244. Thus we hypothesized that dual inhibition of both downstream MEK and AKT pathways would induce synergistic antitumor activity. In this study, we evaluated the efficacy of AZD6244 and MK2206 individually on a large panel of lung cancer cell lines. Then, we treated 28 human lung cancer cell lines with a combination of AZD6244 and MK2206 at clinically applicable drug molar ratios. The AZD6244-MK2206 combination therapy resulted in a synergistic effect on inhibition of lung cancer cell growth compared to the results of single drug treatment alone. MK2206 enhanced AZD6244-induced Bim overexpression and apoptosis in A549 and H157 cells. When we tested the combination of AZD6244 and MK2206 at ratios of 8:1, 4:1, 2:1, and 1:8, we found that the synergistic effect of the combination therapy was ratio-dependent. At ratios of 8:1, 4:1, and 2:1, the drug combination consistently demonstrated synergy, whereas decreasing the ratio to 1:8 resulted in a loss of synergy and produced an additive or antagonistic effect in most cell lines. Furthermore, the AZD6244-MK2206 combination therapy showed synergy in the suppression of A549 and H157 xenograft tumor growth and increased mean animal survival time. The AZD6244-MK2206 combination therapy resulted in effective inhibition of both p-ERK and p-AKT expression in tumor tissue. In addition, a significant increase of apoptosis was detected in tumor tissue from mice treated with AZD6244-MK2206 compared with that from the single agent treated mice. Our study suggests that the combination of AZD6244 and MK2206 has a significant synergistic effect on tumor growth in vitro and in vivo and leads to increased survival rates in mice bearing highly aggressive human lung tumors.
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