Jung-Yaw Lin
Verified @ntu.edu.tw
Institute of Biochemistry and Molecular Biology
National Taiwan University, College of Medicine
RESEARCH INTERESTS
Molecular Biology, Protein Chemistry, Functional Genomics, Biotechnology, Anit-Cancer Drug, and Neuro Protection Drug
Scopus Publications
Scopus Publications
Hei-Jen Huang, Ching-Yi Huang, Mingchung Lee, Jung-Yaw Lin, and Hsiu Mei Hsieh-Li
World Scientific Pub Co Pte Lt
To evaluate the therapeutic effects of Chinese herbal medicine (CHM) for Alzheimer’s disease (AD), we evaluated five CHMs in oligomeric A[Formula: see text]-treated mouse primary hippocampal neuronal cultures. The aqueous extract from the root of Pueraria lobata (Puerariae Radix; PR) showed better neuroprotective effects than did the other four CHM aqueous extracts, including Gardenia jasminoides, Eleutherococcus senticosus, Rhodiola rosea, and Panax, in the primary culture treated with saline or oligomeric A[Formula: see text]. Furthermore, the neuroprotective effects of aqueous extract of PR were also better than its well-known active compound, puerarin, against the neurotoxicity of oligomeric A[Formula: see text] in a primary culture. For in vivo experiments, C57BL/6J male mice that received direct infusion of soluble oligomeric A[Formula: see text] into the bilateral hippocampal CA1 subregion were used as an alternative AD mouse model. The effects and molecular mechanisms of chronic systemic administration of PR aqueous extract were evaluated in the alternative AD model. PR aqueous extract prevented anxiety and cognitive impairment in mice associated with a decrease in the levels of A[Formula: see text] deposition, tau protein phosphorylation, inflammation, loss of noradrenergic, and serotonergic neurons and an increase in the levels of synaptophysin and insulin degrading enzyme (IDE) against the toxicity of oligomeric A[Formula: see text]. Furthermore, no obvious damage to the liver and kidney was detected after chronic systemic administration of PR aqueous extract. Therefore, using PR could be a safer, more effective therapeutic strategy than using its active compound puerarin to prevent both cognitive and noncognitive dysfunction and related pathological features of AD.
I-Cheng Chen, Chia-Ning Chang, Wan-Ling Chen, Te-Hsien Lin, Chih-Ying Chao, Chih-Hsin Lin, Hsuan-Yuan Lin, Mei-Ling Cheng, Mu-Chun Chiang, Jung-Yaw Lin,et al.
World Scientific Pub Co Pte Lt
Nine autosomal dominant spinocerebellar ataxias (SCAs) are caused by an abnormal expansion of CAG trinucleotide repeats that encodes a polyglutamine (polyQ) tract within different genes. Accumulation of aggregated mutant proteins is a common feature of polyQ diseases, leading to progressive neuronal dysfunction and degeneration. SCA type 3 (SCA3), the most common form of SCA worldwide, is characterized by a CAG triplet expansion in chromosome 14q32.1 ATXN3 gene. As accumulation of the mutated polyQ protein is a possible initial event in the pathogenic cascade, clearance of aggregated protein by ubiquitin proteasome system (UPS) has been proposed to inhibit downstream detrimental events and suppress neuronal cell death. In this study, Chinese herbal medicine (CHM) extracts were studied for their proteasome-activating, polyQ aggregation-inhibitory and neuroprotective effects in GFPu and ATXN3/Q[Formula: see text]-GFP 293/SH-SY5Y cells. Among the 14 tested extracts, 8 displayed increased proteasome activity, which was confirmed by 20S proteasome activity assay and analysis of ubiquitinated and fused GFP proteins in GFPu cells. All the eight extracts displayed good aggregation-inhibitory potential when tested in ATXN3/Q[Formula: see text]-GFP 293 cells. Among them, neuroprotective effects of five selected extracts were shown by analyses of polyQ aggregation, neurite outgrowth, caspase 3 and proteasome activities, and ATXN3-GFP, ubiquitin, BCL2 and BAX protein levels in neuronal differentiated ATXN3/Q[Formula: see text]-GFP SH-SY5Y cells. Finally, enhanced proteasome function, anti-oxidative activity and neuroprotection of catalpol, puerarin and daidzein (active constituents of Rehmannia glutinosa and Pueraria lobata) were demonstrated in GFPu and/or ATXN3/Q[Formula: see text]-GFP 293/SH-SY5Y cells. This study may have therapeutic implication in polyQ-mediated disorders.
Yu-Huei Liu, Yui-Ping Weng, Hsin-Ying Tsai, Chao-Jung Chen, Der-Yen Lee, Ching-Liang Hsieh, Yang-Chang Wu, and Jung-Yaw Lin
Elsevier BV
Ya-Jen Chiu, Chi-Mei Lee, Te-Hsien Lin, Hsuan-Yuan Lin, Shin-Ying Lee, Mina Mesri, Kuo-Hsuan Chang, Jung-Yaw Lin, Guey-Jen Lee-Chen, and Chiung-Mei Chen
World Scientific Pub Co Pte Lt
Amyloid [Formula: see text] (A[Formula: see text]) plays a major role in the pathogenesis of Alzheimer’s disease (AD). The accumulation of misfolded A[Formula: see text] causes oxidative and inflammatory damage leading to apoptotic cell death. Chinese herbal medicine (CHM) has been widely used in clinical practice to treat neurodegenerative diseases associated with oxidative stress and neuroinflammation. This study examined the neuroprotection effects of CHM extract Glycyrrhiza inflata (G. inflata) and its active constituents, licochalcone A and liquiritigenin in AD. We examined A[Formula: see text] aggregation inhibition, anti-oxidation and neuroprotection in Tet-On A[Formula: see text]-GFP 293/SH-SY5Y cells and anti-inflammatory potential in lipopolysaccharide (LPS)-stimulated RAW 264.7 and LPS and interferon (IFN)-[Formula: see text] (LPS/IFN-[Formula: see text])-activated BV-2 cells. In addition, we applied conditioned media (CM) of BV-2 cells primed with LPS/IFN-[Formula: see text] to A[Formula: see text]-GFP SH-SY5Y cells to uncover the neuroprotective mechanisms. Our results showed that G. inflata extract and its two constituents displayed potentials of A[Formula: see text] aggregation inhibition and radical-scavenging in biochemical assays, A[Formula: see text] misfolding inhibition and reactive oxygen species (ROS) reduction in A[Formula: see text]-GFP 293 cells, as well as neurite outgrowth promotion, acetylcholinesterase inhibition and SOD2 up-regulation in A[Formula: see text]-GFP SH-SY5Y cells. Meanwhile, both G. inflata extract and its constituents suppressed NO, TNF-[Formula: see text], IL-1[Formula: see text], PGE2 and/or Iba1 productions in inflammation-stimulated RAW 264.7 or BV-2 cells. G. inflata extract and its constituents further protected A[Formula: see text]-GFP SH-SY5Y cells from BV-2 CM-induced cell death by ameliorating reduced BCL2 and attenuating increased IGFBP2, cleaved CASP3, BAD and BAX. Collectively, G. inflata extract, licochalcone A and liquiritigenin display neuroprotection through exerting anti-oxidative and anti-inflammatory activities to suppress neuronal apoptosis.
Tsung-Wei Su, Chao-Yu Yang, Wen-Pin Kao, Bai-Jiun Kuo, Shan-Meng Lin, Jung-Yaw Lin, Yu-Chih Lo, and Su-Chang Lin
Elsevier BV
Yu-Huei Liu, Yui-Ping Weng, Hsuan-Yuan Lin, Sai-Wen Tang, Chao-Jung Chen, Chi-Jung Liang, Chung-Yu Ku, and Jung-Yaw Lin
Springer Science and Business Media LLC
Hepatocellular carcinoma (HCC) remains the leading cause of cancer mortality with limited therapeutic targets. The endoplasmic reticulum (ER) plays a pivotal role in maintaining proteostasis in normal cells. However, alterations in proteostasis are often found in cancer cells, making it a potential target for therapy. Polygonum bistorta is used in traditional Chinese medicine owing to its anticancer activities, but the molecular and pharmacological mechanisms remain unclear. Using hepatoma cells as a model system, this study demonstrated that P. bistorta aqueous extract (PB) stimulated ER stress by increasing autophagosomes but by blocking degradation, followed by the accumulation of ubiquitinated proteins and cell apoptosis. In addition, an autophagy inhibitor did not enhance ubiquitinated protein accumulation whereas a reactive oxygen species (ROS) scavenger diminished both ubiquitinated protein accumulation and ligand-stimulated epidermal growth factor receptor (EGFR) expression, suggesting that ROS generation by PB may be upstream of PB-triggered cell death. Nevertheless, PB-exerted proteostasis impairment resulted in cytoskeletal changes, impairment of cell adhesion and motility, and inhibition of cell cycle progression. Oral administration of PB delayed tumour growth in a xenograft model without significant body weight loss. These findings indicate that PB may be a potential new alternative or complementary medicine for HCC.
Ding-Siang Huang, Yu-Chen Yu, Chung-Hsin Wu, and Jung-Yaw Lin
Hindawi Limited
One of the pathogenic systems of Alzheimer’s disease (AD) is the formation ofβ-amyloid plaques in the brains of patients, and amyloidogenic activity becomes one of the therapeutic targets. Here, we report wogonin, one of the major active constituting components inScutellaria baicalensis, which has the neuroprotective effects on amyloid-βpeptides- (Aβ-) induced toxicity. Oral wogonin treatment improved the performance of triple transgenic AD mice (h-APPswe, h-Tau P301L, and h-PS1 M146V) on the Morris water maze, Y-maze, and novel object recognition. Furthermore, wogonin activated the neurite outgrowth of AD cells by increasing neurite length and complexity of Tet-On Aβ42-GFP SH-SY5Y neuroblastoma cells (AD cells) and attenuated amyloidogenic pathway by decreasing the levels ofβ-secretase, APPβ-C-terminal fragment, Aβ-aggregation, and phosphorylated Tau. Wogonin also increased mitochondrial membrane potential (∆ψm) and protected against apoptosis by reducing the expression of Bax and cleaved PARP. Collectively, these results conclude that wogonin may be a promising multifunctional drug candidate for AD.
Guey-Jen Lee-Chen, Kuo-Hsuan Chang, I-Cheng Chen, Husan-Yuan Lin, Hsuan-Chiang Chen, Chih-Hsin Lin, Te-Hsien Lin, Yu-Ting Weng, Chih-Ying Chao, Yih-Ru Wu,et al.
Informa UK Limited
Background Alzheimer’s disease (AD) and several neurodegenerative disorders known as tauopathies are characterized by misfolding and aggregation of tau protein. Although several studies have suggested the potential of traditional Chinese medicine (TCM) as treatment for neurodegenerative diseases, the role of TCM in treating AD and tauopathies have not been well explored. Materials and methods Tau protein was coupled to the DsRed fluorophore by fusing a pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) with DsRed. The ΔK280 tauRD-DsRed fusion gene was then used to generate Tet-On 293 and SH-SY5Y cell clones as platforms to test the efficacy of 39 aqueous extracts of TCM in reducing tau misfolding and in neuroprotection. Results Seven TCM extracts demonstrated a significant reduction in tau misfolding and reactive oxidative species with low cytotoxicity in the ΔK280 tauRD-DsRed 293 cell model. Glycyrrhiza inflata and Panax ginseng also demonstrated the potential to improve neurite outgrowth in the ΔK280 tauRD-DsRed SH-SY5Y neuronal cell model. G. inflata further rescued the upregulation of ERN2 (pro-apoptotic) and downregulation of unfolded-protein-response-mediated chaperones ERP44, DNAJC3, and SERP1 in ΔK280 tauRD-DsRed 293 cells. Conclusion This in vitro study provides evidence that G. inflata may be a novel therapeutic for AD and tauopathies. Future applications of G. inflata on animal models of AD and tauopathies are warranted to corroborate its effect of reducing misfolding and potential disease modification.
Chung-Hsin Wu, Ding-Siang Huang, Husan-Yuan Lin, Guey-Jen Lee-Chen, Hsiu-Mei Hsieh, and Jung-Yaw Lin
Informa UK Limited
Spinocerebellar ataxia type 17 (SCA 17) is a polyglutamine disease caused by the expansion of CAG/CAA repeats in the TATA box-binding protein (TBP) gene. The Ginkgo biloba extract, EGb 761, contains flavonoids and terpenoids with a potential use for the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. The neuroprotective effects of EGb 761 are obvious, but whether the EGb 761 has therapeutic effects in SCA 17 is still unclear. To manage our issues, we have generated TBP/79Q-expressing SH-SY5Y cells and SCA 17 transgenic mice with the mutant hTBP gene. In in vitro experiment, we observed that the EGb 761 treatment decreased the amount of sodium dodecyl sulfate-insoluble proteins in the TBP/79Q-expressing SH-SY5Y cells. We further found that the EGb 761 treatment could inhibit excitotoxicity and calcium influx and reduce the expression of apoptotic markers in glutamate-treated SH-SY5Y neuroblastoma cells. In in vivo experiment, we observed that the EGb 761 treatment (100 mg/kg intraperitoneal injection per day) could relieve the motor deficiencies of the SCA 17 transgenic mice. Our findings provide evidence that the EGb 761 treatment can be a remedy for SCA 17 via suppressing excitotoxicity and apoptosis in SCA 17 cell and animal models. Therefore, we suggest that EGb 761 may be a potential therapeutic agent for treating SCA 17.
Kuo-Hsuan Chang, Ya-Jen Chiu, Shu-Ling Chen, Chen-Hsiang Huang, Chih-Hsin Lin, Te-Hsien Lin, Chi-Mei Lee, Chintakunta Ramesh, Chung-Hsin Wu, Chin-Chang Huang,et al.
Elsevier BV
Chung-Yu Ku, Yu-Huei Liu, Hsuan-Yuan Lin, Shao-Chun Lu, and Jung-Yaw Lin
Impact Journals, LLC
Liver fatty acid-binding protein (L-FABP) is abundant in hepatocytes and known to be involved in lipid metabolism. Overexpression of L-FABP has been reported in various cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated L-FABP and its association with vascular endothelial growth factors (VEGFs) in 90 HCC patients. We found that L-FABP was highly expressed in their HCC tissues, and that this expression was positively correlated with that of VEGF-A. Additionally, L-FABP significantly promoted tumor growth and metastasis in a xenograft mouse model. We also assessed the mechanisms of L-FABP activity in tumorigenesis; L-FABP was found to associate with VEGFR2 on membrane rafts and subsequently activate the Akt/mTOR/P70S6K/4EBP1 and Src/FAK/cdc42 pathways, which resulted in up-regulation of VEGF-A accompanied by an increase in both angiogenic potential and migration activity. Our results thus suggest that L-FABP could be a potential target for HCC chemotherapy.
Chung-Yu Ku, Ying-Ren Wang, Hsuan-Yuan Lin, Shao-Chun Lu, and Jung-Yaw Lin
Public Library of Science (PLoS)
Inhibition of VEGFR2 activity has been proposed as an important strategy for the clinical treatment of hepatocellular carcinoma (HCC). In this study, we identified corosolic acid (CA), which exists in the root of Actinidia chinensis, as having a significant anti-cancer effect on HCC cells. We found that CA inhibits VEGFR2 kinase activity by directly interacting with the ATP binding pocket. CA down-regulates the VEGFR2/Src/FAK/cdc42 axis, subsequently decreasing F-actin formation and migratory activity in vitro. In an in vivo model, CA exhibited an effective dose (5 mg/kg/day) on tumor growth. We further demonstrate that CA has a synergistic effect with sorafenib within a wide range of concentrations. In conclusion, this research elucidates the effects and molecular mechanism for CA on HCC cells and suggests that CA could be a therapeutic or adjuvant strategy for patients with aggressive HCC.
Guan-Chiun Lee, Chih-Hsin Lin, Yu-Chen Tao, Jinn-Moon Yang, Kai-Cheng Hsu, Yin-Jung Huang, Shih-Han Huang, Pin-Jui Kung, Wan-Ling Chen, Chien-Ming Wang,et al.
Elsevier BV
Guey-Jen Lee-Chen, Pin-Jui Kung, Yu-Chen Tao, Ho-Chiang Hsu, Donala Janreddy, Ching-Fa Yao, Jung-Yaw Lin, Ming-Tsan Su, Chung-Hsin Wu, Hsiu-Mei Hsieh-Li,et al.
Informa UK Limited
In spinocerebellar ataxia type 17 (SCA17), the expansion of a translated CAG repeat in the TATA box binding protein (TBP) gene results in a long polyglutamine (polyQ) tract in the TBP protein, leading to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On SH-SY5Y cells with inducible SCA17 TBP/Q79-green fluorescent protein (GFP) expression to test indole and synthetic derivative NC001-8 for neuroprotection. We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q79 cells. The effects on promoting neurite outgrowth and on reduction of aggregation on Purkinje cells were also confirmed with cerebellar primary and slice cultures of SCA17 transgenic mice. Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment.
Kuo-Hsuan Chang, Wan-Ling Chen, Yih-Ru Wu, Te-Hsien Lin, Yi-Ci Wu, Chih-Ying Chao, Jung-Yaw Lin, Li-Ching Lee, Yi-Chun Chen, Guey-Jen Lee-Chen,et al.
Elsevier BV
Chiung-Mei Chen, Yu-Ting Weng, Wan-Ling Chen, Te-Hsien Lin, Chih-Ying Chao, Chih-Hsin Lin, I-Cheng Chen, Li-Ching Lee, Hsuan-Yuan Lin, Yih-Ru Wu,et al.
Elsevier BV
Tien-Chun Wang, Chih-Nan Fang, Chih-Chien Shen, Hui-Yu Wei, Yui-Ping Weng, Jung-Yaw Lin, Hsiu Mei Hsieh-Li, and Chen-Yu Lee
Hindawi Limited
Lung cancer has long been one of the most deadly forms of cancer. The majority of lung cancers are of the non-small-cell lung cancer (NSCLC) type. Here we used the non-small-cell lung carcinoma cell line A549 to screen 15 different traditional Chinese herbal medicine (CHM) formulae to explore the possible mechanisms of alternative medicine in lung cancer therapy. We identified three formulae (Formulae 3, 5, and 14) that substantially decreased the survival of A549 cells but did not affect MRC5 normal lung tissue cells. Formula 14, Yang-Dan-Tang, a modified decoction of Ramulus Cinnamomi Cassiae, was chosen for further characterization. Flow cytometry analysis showed that treatment of Formula 14 induced cell cycle arrest in G1 and G2 phase without causing significant cell death. These results were also confirmed by Western blot analysis, with decreased expression of G1/S and G2/M promoting cell cycle machinery including cyclin D3, cyclin B1, CDK4, and CDK6. This study provides further insight into the possible working mechanism of Yang-Dan-Tang in patients.
Sai-Wen Tang and Jung-Yaw Lin
Hindawi Limited
Clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC, is characterized by high metastasis potential and strong resistance to traditional therapies, resulting in a poor five-year survival rate of patients. Several therapies targeted to VEGF pathway for advanced RCC have been developed, however, it still needs to discover new therapeutic targets for treating RCC. Genome-wide gene expression analyses have been broadly used to identify unknown molecular mechanisms of cancer progression. Recently, we applied the oligo-capping method to construct the full-length cDNA libraries of ccRCC and adjacent normal kidney, and analyzed the gene expression profiles by high-throughput sequencing. This paper presents a review for recent findings on therapeutic potential of MYC pathway and nicotinamide N-methyltransferase for the treatment of RCC.
Li-Ching Lee, Chiung-Mei Chen, Hao-Chun Wang, Hsiao-Han Hsieh, I-Sheng Chiu, Ming-Tsan Su, Hsiu-Mei Hsieh-Li, Chung-Hsin Wu, Guan-Chiun Lee, Guey-Jen Lee-Chen,et al.
Public Library of Science (PLoS)
Spinocerebellar ataxia 17 (SCA17) is caused by expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) that is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The precise pathogenic mechanism in SCA17 remains unclear. Previously proteomics study using a cellular model of SCA17 has revealed reduced expression of heat shock 70 kDa protein 5 (HSPA5) and heat shock 70 kDa protein 8 (HSPA8), suggesting that impaired protein folding may contribute to the cell dysfunction of SCA17 (Lee et al., 2009). In lymphoblastoid cells, HSPA5 and HSPA8 expression levels in cells with mutant TBP were also significantly lower than that of the control cells (Chen et al., 2010). As nuclear transcription factor Y (NFY) has been reported to regulate HSPA5 transcription, we focused on if NFY activity and HSPA5 expression in SCA17 cells are altered. Here, we show that TBP interacts with NFY subunit A (NFYA) in HEK-293 cells and NFYA incorporated into mutant TBP aggregates. In both HEK-293 and SH-SY5Y cells expressing TBP/Q(61~79), the level of soluble NFYA was significantly reduced. In vitro binding assay revealed that the interaction between TBP and NFYA is direct. HSPA5 luciferase reporter assay and endogenous HSPA5 expression analysis in NFYA cDNA and siRNA transfection cells further clarified the important role of NFYA in regulating HSPA5 transcription. In SCA17 cells, HSPA5 promoter activity was activated as a compensatory response before aggregate formation. NFYA dysfunction was indicated in SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate formation. Because essential roles of HSPA5 in protection from neuronal apoptosis have been shown in a mouse model, NFYA could be a target of mutant TBP in SCA17.
Shih-Chin Wang, Sai-Wen Tang, Sio-Hong Lam, Chung-Chieh Wang, Yu-Huei Liu, Hsuan-Yuan Lin, Shoei-Sheng Lee, and Jung-Yaw Lin
Hindawi Limited
Renal cell carcinoma (RCC) cells are characterized by strong drug resistance and high metastatic incidence. In this study, the effects of ten kinds of Chinese herbs on RCC cell migration and proliferation were examined. Aqueous extract ofPaeonia suffruticosa(PS-A) exerted strong inhibitory effects on cancer cell migration, mobility, and invasion. The results of mouse xenograft experiments showed that the treatment of PS-A significantly suppressed tumor growth and pulmonary metastasis. We further found that PS-A markedly decreased expression of VEGF receptor-3 (VEGFR-3) and phosphorylation of FAK in RCC cells. Moreover, the activation of Rac-1, a modulator of cytoskeletal dynamics, was remarkably reduced by PS-A. Additionally, PS-A suppressed polymerization of actin filament as demonstrated by confocal microscopy analysis and decreased the ratio of F-actin to G-actin in RCC cells, suggesting that PS-A inhibits RCC cell migration through modulating VEGFR-3/FAK/Rac-1 pathway to disrupt actin filament polymerization. In conclusion, this research elucidates the effects and molecular mechanism for antimigration of PS-A on RCC cells and suggests PS-A to be a therapeutic or adjuvant strategy for the patients with aggressive RCC.
Yu-Huei Liu, Meng-Luen Li, Meng-Yu Hsu, Ya-Yueh Pang, I-Ling Chen, Ching-Kuei Chen, Sai-Wen Tang, Hsuan-Yuan Lin, and Jung-Yaw Lin
Hindawi Limited
Aeginetia indicaLinn. (Guan-Jen-Huang, GJH), a traditional Chinese herb, has the potential to be an immunomodulatory agent. The purpose of this study was to explore the effect of GJH in the treatment of renal cancer. Concentration-effect curves for the influence of GJH on cellular proliferation showed a biphasic shape. Besides, GJH had a synergistic effect on cytotoxicity when combined with 5-fluorouracil (5-FU)which may be due to the alternation of the chemotherapeutic agent resistance-related genes and due to the synergistic effects on apoptosis. In addition, treatment with GJH extract markedly reduced 786-O cell adherence to human umbilical vein endothelial cells (HUVECs) and decreased 786-O cell migration and invasion. In a xenograft animal model, GJH extract had an inhibitory effect on tumor cell-induced metastasis. Moreover, western blot analysis showed that the expression of intercellular adhesion molecule-1 (ICAM-1) in 786-O cells was significantly decreased by treatment with GJH extract through inactivation of nuclear factor-κB (NF--κB). These results suggest that GJH extract has a synergistic effect on apoptosis induced by chemotherapeutic agents and an inhibitory effect on cell adhesion, migration, and invasion, providing evidence for the use of water-based extracts of GJH as novel alternative therapeutic agents in the treatment of human renal cancer.
Yu-Huei Liu, Konan Peck, and Jung-Yaw Lin
Hindawi Limited
Abrin (ABR), a protein purified from the seeds ofAbrus precatorius, induces apoptosis in various types of cancer cells. However, the detailed mechanism remains largely uncharacterized. By using a cDNA microarray platform, we determined that prohibitin (PHB), a tumor suppressor protein, is significantly upregulated in ABR-triggered apoptosis. ABR-induced upregulation of PHB is mediated by the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway, as demonstrated by chemical inhibitors. In addition, ABR significantly induced the expression of Bax as well as the activation of caspase-3 and poly(ADP-ribose) polymerase (PARP) in Jurkat T cells, whereas the reduction of PHB by specific RNA interference delayed ABR-triggered apoptosis through the proapoptotic genes examined. Moreover, our results also indicated that nuclear translocation of the PHB-p53 complex may play a role in the transcription of Bax. Collectively, our data show that PHB plays a role in ABR-induced apoptosis, which may be helpful for the development of diagnostic or therapeutic agents.
Sai-Wen Tang, Tsung-Cheng Yang, Wei-Chou Lin, Wen-Hsin Chang, Chung-Chieh Wang, Ming-Kuen Lai, and Jung-Yaw Lin
Oxford University Press (OUP)
Nicotinamide N-methyltransferase (NNMT) was recently identified as one clear cell renal cell carcinoma (ccRCC)-associated gene by analyzing full-length complementary DNA-enriched libraries of ccRCC tissues. The aim of this study is to investigate the potential role of NNMT in cellular invasion. A strong NNMT expression is accompanied with a high invasive activity in ccRCC cell lines, and small interfering RNA-mediated NNMT knockdown effectively suppressed the invasive capacity of ccRCC cells, whereas NNMT overexpression markedly enhanced that of human embryonic kidney 293 (HEK293) cells. A positive correlation between the expression of NNMT and matrix metallopeptidase (MMP)-2 was found in ccRCC cell lines and clinical tissues. The treatment of blocking antibody or inhibitor specific to MMP-2 significantly suppressed NNMT-dependent cellular invasion in HEK293 cells. Furthermore, SP-1-binding region of MMP-2 promoter was found to be essential in NNMT-induced MMP-2 expression. The specific inhibitors of PI3K/Akt signaling markedly decreased the binding of SP1 to MMP-2 promoter as shown by chromatin immunoprecipitation assay. We also demonstrated that PI3K/Akt pathway plays a role in NNMT-dependent cellular invasion and MMP-2 activation. Moreover, short hairpin RNA-mediated knockdown of NNMT expression efficiently inhibited the growth and metastasis of ccRCC cells in non-obese diabetic severe combined immunodeficiency mice. Taken together, the present study suggests that NNMT has a crucial role in cellular invasion via activating PI3K/Akt/SP1/MMP-2 pathway in ccRCC.
June H. Wu, Albert M. Wu, Zhangung Yang, Yuen-Yuen Chen, Biswajit Singha, Lu-Ping Chow, and Jung-Yaw Lin
Elsevier BV
Jack Cheng, Tian-Huey Lu, Chao-Lin Liu, and Jung-Yaw Lin
Springer Science and Business Media LLC
Abstract X-ray crystal structure determination of agglutinin from abrus precatorius in Taiwan is presented. The crystal structure of agglutinin, a type II ribosome-inactivating protein (RIP) from the seeds of Abrus precatorius in Taiwan, has been determined from a novel crystalline form by the molecular replacement method using the coordinates of abrin-a as the template. The structure has space group P41212 with Z = 8, and been refined at 2.6 Å to R-factor of 20.4%. The root-mean-square deviations of bond lengths and angles from the standard values are 0.009 Å and 1.3°. Primary, secondary, tertiary and quaternary structures of agglutinin have been described and compared with those of abrin-a to a certain extent. In subsequent docking research, we found that Asn200 of abrin-a may form a critical hydrogen bond with G4323 of 28SRNA, while corresponding Pro199 of agglutinin is a kink hydrophobic residue bound with the cleft in a more compact complementary relationship. This may explain the lower toxicity of agglutinin than abrin-a, despite of similarity in secondary structure and the activity cleft of two RIPs.