scholarly journals Impairment of Membrane Lipid Homeostasis by Bichalcone Analog TSWU-BR4 Attenuates Function of GRP78 in Regulation of the Oxidative Balance and Invasion of Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 371
Author(s):  
Tsung-Lin Lee ◽  
Shyang-Guang Wang ◽  
Wen-Ling Chan ◽  
Ching-Hsiao Lee ◽  
Tian-Shung Wu ◽  
...  

The specialized cholesterol/sphingolipid-rich membrane domains termed lipid rafts are highly dynamic in the cancer cells, which rapidly assemble effector molecules to form a sorting platform essential for oncogenic signaling transduction in response to extra- or intracellular stimuli. Density-based membrane flotation, subcellular fractionation, cell surface biotinylation, and co-immunoprecipitation analyses of bichalcone analog ((E)-1-(4-Hydroxy-3-((4-(4-((E)-3-(pyridin-3-yl)acryloyl)phenyl)piperazin-1-yl)methyl)phenyl)-3-(pyridin-3-yl)prop-2-en-1-one (TSWU-BR4)-treated cancer cells showed dissociation between GRP78 and p85α conferring the recruitment of PTEN to lipid raft membranes associated with p85α. Ectopic expression of GRP78 could overcome induction of lipid raft membrane-associated p85α–unphosphorylated PTEN complex formation and suppression of GRP78−PI3K−Akt−GTP-Rac1-mediated and GRP78-regulated PERK−Nrf2 antioxidant pathway and cancer cell invasion by TSWU-BR4. Using specific inducer, inhibitor, or short hairpin RNA for ASM demonstrated that induction of the lipid raft membrane localization and activation of ASM by TSWU-BR4 is responsible for perturbing homeostasis of cholesterol and ceramide levels in the lipid raft and ER membranes, leading to alteration of GRP78 membrane trafficking and subsequently inducing p85α–unphosphorylated PTEN complex formation, causing disruption of GRP78−PI3K−Akt−GTP-Rac1-mediated signal and ER membrane-associated GRP78-regulated oxidative stress balance, thus inhibiting cancer cell invasion. The involvement of the enrichment of ceramide to lipid raft membranes in inhibition of NF-κB-mediated MMP-2 expression was confirmed through attenuation of NF-κB activation using C2-ceramide, NF-κB specific inhibitors, ectopic expression of NF-κB p65, MMP-2 promoter-driven luciferase, and NF-κB-dependent reporter genes. In conclusion, localization of ASM in the lipid raft membranes by TSWU-BR4 is a key event for initiating formation of ceramide-enriched lipid raft membrane platforms, which causes delocalization of GRP78 from the lipid raft and ER membranes to the cytosol and formation of p85α–unphosphorylated PTEN complexes to attenuate the GRP78-regulated oxidative stress balance and GRP78−p85α−Akt−GTP-Rac1−NF-κB−MMP-2-mediated cancer cell invasion.

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2745
Author(s):  
Miran Jeong ◽  
Yi-Yue Wang ◽  
Ju-Yeon Choi ◽  
Myong-Cheol Lim ◽  
Jung-Hye Choi

In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.


2005 ◽  
Vol 15 (11) ◽  
pp. 1685-1734 ◽  
Author(s):  
M. A. J. CHAPLAIN ◽  
G. LOLAS

The growth of solid tumours proceeds through two distinct phases: the avascular and the vascular phase. It is during the latter stage that the insidious process of cancer invasion of peritumoral tissue can and does take place. Vascular tumours grow rapidly allowing the cancer cells to establish a new colony in distant organs, a process that is known as metastasis. The progression from a single, primary tumour to multiple tumours in distant sites throughout the body is known as the metastatic cascade. This is a multistep process that first involves the over-expression by the cancer cells of proteolytic enzyme activity, such as the urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs). uPA itself initiates the activation of an enzymatic cascade that primarily involves the activation of plasminogen and subsequently its matrix degrading protein plasmin. Degradation of the matrix then enables the cancer cells to migrate through the tissue and subsequently to spread to secondary sites in the body. In this paper we consider a mathematical model of cancer cell invasion of tissue (extracellular matrix) which focuses on the role of the plasminogen activation system. The model consists of a system of reaction-diffusion-taxis partial differential equations describing the interactions between cancer cells, urokinase plasminogen activator (uPA), uPA inhibitors, plasmin and the host tissue. The focus of the modelling is on the spatio-temporal dynamics of the uPA system and how this influences the migratory properties of the cancer cells through random motility, chemotaxis and haptotaxis. The results obtained from numerical computations carried out on the model equations produce rich, dynamic heterogeneous spatio-temporal solutions and demonstrate the ability of rather simple models to produce complicated dynamics, all of which are associated with tumour heterogeneity and cancer cell progression and invasion.


2009 ◽  
Vol 284 (1) ◽  
pp. 80-85 ◽  
Author(s):  
Severin Pinilla ◽  
Eckhard Alt ◽  
F.J. Abdul Khalek ◽  
Constantin Jotzu ◽  
Fabian Muehlberg ◽  
...  

Author(s):  
Marija Plodinec ◽  
Philipp Oertle ◽  
Alexandre Glentis ◽  
Danijela Vignjevic ◽  
Olivier Ganier ◽  
...  

2016 ◽  
Vol 55 (12) ◽  
pp. 2106-2120 ◽  
Author(s):  
Hui-Li Lu ◽  
Shih-Shun Chen ◽  
Wen-Tung Hsu ◽  
Yao-Cheng Lu ◽  
Chuan-Chun Lee ◽  
...  

2020 ◽  
Vol 21 (21) ◽  
pp. 8153
Author(s):  
Kimin Kim ◽  
Yeh Joo Sohn ◽  
Ruri Lee ◽  
Hye Ju Yoo ◽  
Ji Yoon Kang ◽  
...  

Cancer-associated fibroblasts (CAFs) in the cancer microenvironment play an essential role in metastasis. Differentiation of endothelial cells into CAFs is induced by cancer cell-derived exosomes secreted from cancer cells that transfer molecular signals to surrounding cells. Differentiated CAFs facilitate migration of cancer cells to different regions through promoting extracellular matrix (ECM) modifications. However, in vitro models in which endothelial cells exposed to cancer cell-derived exosomes secreted from various cancer cell types differentiate into CAFs or a microenvironmentally controlled model for investigating cancer cell invasion by CAFs have not yet been studied. In this study, we propose a three-dimensional in vitro cancer cell invasion model for real-time monitoring of the process of forming a cancer invasion site through CAFs induced by exosomes isolated from three types of cancer cell lines. The invasiveness of cancer cells with CAFs induced by cancer cell-derived exosomes (eCAFs) was significantly higher than that of CAFs induced by cancer cells (cCAFs) through physiological and genetic manner. In addition, different genetic tendencies of the invasion process were observed in the process of invading cancer cells according to CAFs. Our 3D microfluidic platform helps to identify specific interactions among multiple factors within the cancer microenvironment and provides a model for cancer drug development.


2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Qi-Hong Jiang ◽  
Ai-Xiang Wang ◽  
Yan Chen

As a member of the ezrin-radixin-moesin (ERM) family, radixin is overexpressed in many tumor tissues. However, little is known about its role in the progression of colon cancer. So we here aimed to determine the function of radixin in colon cancer cell invasion. Interestingly, we found that the expression of radixin was significantly elevated in colon cancer cells. Knockdown of radixin suppressed the invasion and migration of colon cancer cells. Further, knockdown of radixin inhibited the activation of Rac1 and ERK1/2, and decreased the expression and secretion of MMP-7. In addition, Rac1-ERK signaling pathway was required for the radixin-promoted invasion and MMP-7 production. Together, our findings suggest that radixin enhances the invasion and migration of colon cancer cells. Activation of Rac1-ERK pathway and consequent upregulation of MMP-7 production may contribute to the function of radixin in the regulation of colon cancer cell invasion. Thus, radixin may act as a novel target for the diagnosis and treatment of colon cancer.


Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 280
Author(s):  
Laura Bizzozero ◽  
Margherita Pergolizzi ◽  
Davide Pascal ◽  
Elena Maldi ◽  
Giulia Villari ◽  
...  

Many nervous proteins are expressed in cancer cells. In this report, we asked whether the synaptic protein neuroligin 1 (NLGN1) was expressed by prostatic and pancreatic carcinomas; in addition, given the tendency of these tumors to interact with nerves, we asked whether NLGN1 played a role in this process. Through immunohistochemistry on human tissue microarrays, we showed that NLGN1 is expressed by prostatic and pancreatic cancer tissues in discrete stages and tumor districts. Next, we performed in vitro and in vivo assays, demonstrating that NLGN1 promotes cancer cell invasion and migration along nerves. Because of the established role of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) in tumor–nerve interactions, we assessed a potential NLGN1–GDNF cooperation. We found that blocking GDNF activity with a specific antibody completely inhibited NLGN1-induced in vitro cancer cell invasion of nerves. Finally, we demonstrated that, in the presence of NLGN1, GDNF markedly activates cofilin, a cytoskeletal regulatory protein, altering filopodia dynamics. In conclusion, our data further prove the existence of a molecular and functional cross-talk between the nervous system and cancer cells. NLGN1 was shown here to function along one of the most represented neurotrophic factors in the nerve microenvironment, possibly opening new therapeutic avenues.


2009 ◽  
Vol 69 (22) ◽  
pp. 8585-8593 ◽  
Author(s):  
Y.-F. Chen ◽  
C.-Y. Chou ◽  
R. J. Wilkins ◽  
J. C. Ellory ◽  
D. B. Mount ◽  
...  

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