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knock down of GRP78

Xiaojing Nie, Melinda A Chanley, Ruma Pengal, David B Thomas, Shipra Agrawal, William E Smoyer
The p38MAPK pathway plays a crucial role in various glomerulopathies, with activation being associated with disease and inhibition being associated with disease amelioration. We hypothesized that the downstream targets of p38MAPK, MK2 and/or MK3, play an important role in mediating injury in experimental nephrotic syndrome via their actions on their downstream substrates HSPB1 and COX-2. To test this hypothesis, the effects of both pharmacological and genetic inhibition of MK2 and MK3 were examined in mouse Adriamycin (ADR) and rat puromycin aminonucleoside (PAN) nephropathy models...
November 29, 2017: American Journal of Physiology. Renal Physiology
Tien-Huang Chen, Yi-Hsuan Chiang, Jiun-Nan Hou, Chih-Chieh Cheng, Eny Sofiyatun, Cheng-Hsun Chiu, Wei-June Chen
Dengue viruses (DENVs) cause dengue fever which is an important mosquito-borne disease in tropical areas. Generally, DENV does not cause cellular damage in mosquito cells. However, alterations in cytosolic calcium ions ([Ca(2+)]cyt) and the mitochondrial membrane potential (MMP), as well as accumulated reactive oxygen species (ROS), including superoxide anions (O2(∙-)) and hydrogen peroxide (H2O2), can be detected in C6/36 cells with DENV2 infection. Evident upregulation of BiP/GRP78 also appeared at 24 h postinfection in DENV2-infected C6/36 cells...
2017: BioMed Research International
Rui Wang, Da-Zhuang Sun, Chun-Qing Song, Yong-Min Xu, Wei Liu, Zhi Liu, Xue-Song Dong
Paraquat (PQ), as one of the most widely used herbicides in the world, can cause severe lung damage in humans and animals. This study investigated the underlying molecular mechanism of PQ-induced lung cell damage and the protective role of salubrinal. Human lung epithelial-like A549 cells were treated with PQ for 24h and were pre-incubated with salubrinal for 2h, followed by 500μM of PQ treatment. Silencing eIF2α gene of the A549 cells with siRNA interference method was conducted. Cell morphology, cell viability, apoptosis and caspase-3 activity were assessed by different assays accordingly thereafter...
October 3, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Jun Shao, Ying Yin, Xiaowen Yin, Li Ji, Yu Xin, Jian Zou, Yong Yao
BACKGROUND/AIMS: Diabetic retinopathy (DR) is one of the main causes of blindness in the world. Our previous study showed that transthyretin (TTR) regulates key genes in the Tie2 pathway and inhibits the development of neovascularization in DR, but the mechanism is still unclear. Here, we investigated how TTR affects the progression of neovascularization in DR. METHODS: Natural and simulated DR media (hyperglycemia and hypoxia) were used to culture human retinal microvascular endothelial cells (hRECs)...
2017: Cellular Physiology and Biochemistry
Mengting Sheng, Zirui Huang, Liming Pan, Min Yu, Cai Yi, Lin Teng, Ling He, Chen Gu, Chunli Xu, Junming Li
AIMS: This study aimed to investigate potential candidates and molecular mechanisms of myocardial ischemia/reperfusion (I/R) injury (MIRI) in type 2 diabetes mellitus. MAIN METHODS: Type 2 diabetic and myocardial I/R mouse models were established with a high fat-diet (HFD) for 24weeks and subjecting to global ischemia/reperfusion for 1h/3h, respectively. Microarray analysis was applied to screen differentially expressed genes (DEGs) in the hearts of these mice. Moreover, H9c2 cells were treated with high glucose (HG) and/or hypoxia and reoxygenation (H/R)...
November 1, 2017: Life Sciences
Dan Xu, Juliette A Aka, Ruixuan Wang, Sheng-Xiang Lin
17beta-hydroxysteroid dehydrogenase type 5 (17β-HSD5) is an important enzyme associated with sex steroid metabolism in hormone-dependent cancer. However, reports on its expression and its prognostic value in breast cancer are inconsistent. Here, we demonstrate the impact of 17β-HSD5 expression modulation on the proteome of estrogen receptor-positive (ER+) breast cancer cells. RNA interference technique (siRNA) was used to knock down 17β-HSD5 gene expression in the ER+ breast cancer cell line MCF-7 and the proteome of the 17β-HSD5-knockdown cells was compared to that of MCF-7 cells using two-dimensional (2-D) gel electrophoresis followed by mass spectrometry analysis...
July 2017: Journal of Steroid Biochemistry and Molecular Biology
Laurence Booth, Jane L Roberts, Cindy Sander, John Lee, John M Kirkwood, Andrew Poklepovic, Paul Dent
Studies focused on the killing of activated B-RAF melanoma cells by the histone deacetylase (HDAC) inhibitor AR42. Compared to other tumor cell lines, PDX melanoma isolates were significantly more sensitive to AR42-induced killing. AR42 and the multi-kinase inhibitor pazopanib interacted to activate: an eIF2α-Beclin1 pathway causing autophagosome formation; an eIF2α-DR4/DR5/CD95 pathway; and an eIF2α-dependent reduction in the expression of c-FLIP-s, MCL-1 and BCL-XL. AR42 did not alter basal chaperone activity but increased the ability of pazopanib to inhibit HSP90, HSP70 and GRP78...
March 7, 2017: Oncotarget
Yongjie Xiong, Huatao Chen, Pengfei Lin, Aihua Wang, Lei Wang, Yaping Jin
Activating transcription factor 6 (ATF6), a sensor protein located in the endoplasmic reticulum (ER) membrane, is an important factor in the ER stress signaling pathway. ER stress is known to be involved in folliculogenesis, follicular growth, and ovulation; however, the physiological function of ATF6 in mouse granulosa cells remains largely unknown. The aim of this study was to assess the role of ATF6 in mouse granulosa cells with respect to apoptosis, the cell cycle, and steroid hormone production, as well as several key genes related to follicular development, via RNA interference, immunohistochemical staining, real-time quantitative PCR, Western blotting, flow cytometry, terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling (TUNEL) assay, and ELISA...
March 1, 2017: American Journal of Physiology. Cell Physiology
Chan Young Ock, Jong-Min Park, Young-Min Han, Migyeong Jeong, Mi-Young Kim, Ho Jae Lee, Ki Baik Hahm
Non-steroidal anti-inflammatory drug (NSAID)-associated endoplasmic reticulum (ER) stress (a cyclooxygenase-2-independent mechanism) and consequent autophagic cell death are responsible for NSAID-associated gastric damage. Therefore, alleviating cytotoxicity executed via ER stress and autophagy can be a strategy to prevent NSAID-associated gastric damage. Here, we explored whether genetic or pharmacologic inhibition of autophagy can mitigate NSAID-associated gastric damage in in vitro and in vivo models. To examine the effects of genetic inhibition of NSAID-associated autophagy, we administered indomethacin to RGM1 gastric mucosal cells transfected with shPERK, siLC3B, or shATG5 and microtubule-associated protein light chain 3B knock-out (LC3B(-/-)) mice...
April 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Sarah Gordon, Paul Dent
Phosphodiesterase 5 (PDE5) inhibitors prevent the breakdown of cGMP that results in prolonged protein kinase G activation and the generation of nitric oxide. PDE5 inhibitors enhanced the anti-NSCLC cell effects of the NSCLC therapeutic pemetrexed. [Pemetrexed + sildenafil] activated an eIF2α - ATF4 - CHOP - Beclin1 pathway causing formation of toxic autophagosomes; activated a protective IRE1 - XBP-1 - chaperone induction pathway; and activated a toxic eIF2α - CHOP - DR4 / DR5 / CD95 induction pathway. [Pemetrexed + sildenafil] reduced the expression of c-FLIP-s, MCL-1 and BCL-XL that was blocked in a cell-type -dependent fashion by either over-expression of HSP90 / GRP78 / HSP70 / HSP27 or by blockade of eIF2α-CHOP signaling...
January 3, 2017: Oncotarget
Mina Thon, Toru Hosoi, Koichiro Ozawa
Leptin, an adipocyte-derived hormone, centrally regulates energy homeostasis. Overlaps in the regulation of glucose and energy homeostasis have been reported between leptin and insulin. However, the effects of insulin on leptin's actions in the central nervous system (CNS) have not yet been elucidated in detail. In the present study, we found that insulin potentiated leptin's actions through GRP78 in the neuronal cell line, SH-SY5Y-ObRb. Since insulin induces GRP78, we speculated that it may also enhance leptin's actions through this induction...
September 28, 2016: Scientific Reports
Michael J Haas, Luisa Onstead-Haas, Tracey Lee, Maisoon Torfah, Arshag D Mooradian
BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) has been implicated in diabetes-related vascular complications partly through oxidative stress. OBJECTIVE: To determine the role of angiotensin II receptor subtype one (AT1) in dextrose induced endoplasmic reticulum (ER) stress, another cellular stress implicated in vascular disease. METHODS: Human coronary artery endothelial cells with or without AT1 receptor knock down were treated with 27...
October 1, 2016: International Journal of Cardiology
Mehrad Tavallai, Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
We determined whether the approved myelofibrosis drug ruxolitinib (Jakafi(®)), an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could be repurposed as an anti-cancer agent for solid tumors. Ruxolitinib synergistically interacted with dual ERBB1/2/4 inhibitors to kill breast as well as lung, ovarian and brain cancer cells. Knock down of JAK1/2 or of ERBB1/2/3/4 recapitulated on-target drug effects. The combination of (ruxolitinib + ERBB1/2/4 inhibitor) rapidly inactivated AKT, mTORC1, mTORC2, STAT3, and STAT5, and activated eIF2α...
2016: Frontiers in Oncology
Xuefeng Bu, Yinghai Zhao, Zhijian Zhang, Mubin Wang, Mi Li, Yulan Yan
We have reported that the recombinant avirulent Newcastle disease virus (NDV) LaSota strain expressing the rabies virus glycoprotein (rL-RVG) could induce autophagy and apoptosis in gastric carcinoma cells. In the present study, we explored the upstream regulators, endoplasmic reticulum (ER) stress that induce autophagy and apoptosis and the relationships among them. For this purpose, SGC-7901 and HGC cells were infected with rL-RVG. NDV LaSota strain and phosphate-buffered saline (PBS) were treated as the control groups...
2016: American Journal of Cancer Research
Laurence Booth, Thomas Albers, Jane L Roberts, Mehrad Tavallai, Andrew Poklepovic, Iryna O Lebedyeva, Paul Dent
We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization...
June 28, 2016: Oncotarget
Q X Ji, L L Liu, L Li, X M Xing
OBJECTIVE: To investigate the roles of glucose regulated protein 78(GRP78) in proliferation and migration of human colorectal carcinoma cell RKO. METHODS: The colorectal carcinoma cell line RKO was transfected by lentiviral vector pLV-shRNA GRP78 and lentivirus vector pLV-control. MTT test and colony formation assay were used to evaluate the cell proliferation ability. Distribution of cell cycle was analyzed by flow cytometry. Cell migration ability was detected by scratches migration experiment...
June 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
Laurence Booth, Jane L Roberts, Heath Ecroyd, Sarah R Tritsch, Sina Bavari, St Patrick Reid, Stefan Proniuk, Alexander Zukiwski, Abraham Jacob, Claudia S Sepúlveda, Federico Giovannoni, Cybele C García, Elsa Damonte, Javier González-Gallego, María J Tuñón, Paul Dent
We have recently demonstrated that AR-12 (OSU-03012) reduces the function and ATPase activities of multiple HSP90 and HSP70 family chaperones. Combined knock down of chaperones or AR-12 treatment acted to reduce the expression of virus receptors and essential glucosidase proteins. Combined knock down of chaperones or AR-12 treatment inactivated mTOR and elevated ATG13 S318 phosphorylation concomitant with inducing an endoplasmic reticulum stress response that in an eIF2α-dependent fashion increased Beclin1 and LC3 expression and autophagosome formation...
October 2016: Journal of Cellular Physiology
Prashanta Kumar Panda, Birendra Behera, Biswa Ranjan Meher, Durgesh Nandini Das, Subhadip Mukhopadhyay, Niharika Sinha, Prajna Paramita Naik, Bibhas Roy, Joyjyoti Das, Subhankar Paul, Tapas K Maiti, Rajesh Agarwal, Sujit K Bhutia
Abrus agglutinin (AGG), a type II ribosome-inactivating protein has been found to induce mitochondrial apoptosis. In the present study, we documented that AGG-mediated Akt dephosphorylation led to ER stress resulting the induction of autophagy-dependent cell death through the canonical pathway in cervical cancer cells. Inhibition of autophagic death with 3-methyladenine (3-MA) and siRNA of Beclin-1 and ATG5 increased AGG-induced apoptosis. Further, inhibiting apoptosis by Z-DEVD-FMK and N-acetyl cysteine (NAC) increased autophagic cell death after AGG treatment, suggesting that AGG simultaneously induced autophagic and apoptotic death in HeLa cells...
February 2017: Molecular Carcinogenesis
Xiaoping Wang, Qinglong Guo, Lei Tao, Li Zhao, Yan Chen, Teng An, Zhen Chen, Rong Fu
Gastric cancer (GC) is still one of the leading causes of death in cancer-related diseases. In this study, we aimed to investigate the antitumor effect of E Platinum, a newly platinum-based chemotherapeutic agent bearing the basic structure of Oxaliplatin, in a variety of gastric carcinoma cells and the underlying mechanisms. We demonstrated that E Platinum significantly induced apoptosis in gastric cancer cells via mitochondrial apoptotic pathway as a result of increased reactive oxygen species (ROS). We also found that E Platinum enhanced Ca(2+) flux out from the endoplasmic reticulum by increasing the protein expression of IP3R type 1 (IP3R1) and decreasing the expression of ERp44...
January 2017: Molecular Carcinogenesis
Robert Y L Wang, Yu-Jen Wu, Han-Shan Chen, Chih-Jung Chen
Evidence has emerged that RNA viruses utilize the host secretory pathway for processing and trafficking mature viral particles and for exiting the infected cells. Upon completing the complex assembly process, the viral particles take advantage of the cellular secretory trafficking machinery for their intracellular trafficking toward the Golgi organelle and budding or export of virions. In this study, we showed that Japanese encephalitis virus (JEV)-induced extracellular GRP78 contains no KDEL motif using an anti-KDEL-specific antibody...
February 5, 2016: Viruses
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