scholarly journals Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Author(s):  
Niti Kumari ◽  
Somrudee Reabroi ◽  
Brian J. North
Keyword(s):  
Cancer Cells ◽  
Signaling Pathways ◽  
Cancer Cell ◽  
Cancer Biology ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tumor Dissemination

G protein-coupled receptors (GPCRs) represent a large family of transmembrane proteins that transduce an external stimulus into a variety of cellular responses. They play a critical role in various pathological conditions in humans, including cancer, by regulating a number of key processes involved in tumor formation and progression. The epithelial-mesenchymal transition (EMT) is a fundamental process in promoting cancer cell invasion and tumor dissemination leading to metastasis, an often intractable state of the disease. Uncontrolled proliferation and persistent metabolism of cancer cells also induce oxidative stress, hypoxia, and depletion of growth factors and nutrients. These disturbances lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and induce a cellular condition called ER stress (ERS) which is counteracted by activation of the unfolded protein response (UPR). Many GPCRs modulate ERS and UPR signaling via ERS sensors, IRE1α, PERK, and ATF6, to support cancer cell survival and inhibit cell death. By regulating downstream signaling pathways such as NF-κB, MAPK/ERK, PI3K/AKT, TGF-β, and Wnt/β-catenin, GPCRs also upregulate mesenchymal transcription factors including Snail, ZEB, and Twist superfamilies which regulate cell polarity, cytoskeleton remodeling, migration, and invasion. Likewise, ERS-induced UPR upregulates gene transcription and expression of proteins related to EMT enhancing tumor aggressiveness. Though GPCRs are attractive therapeutic targets in cancer biology, much less is known about their roles in regulating ERS and EMT. Here, we will discuss the interplay in GPCR-ERS linked to the EMT process of cancer cells, with a particular focus on oncogenes and molecular signaling pathways.

Effect of JAG2 on migration and invasion in colorectal cancer cell by PRAF2, independent of epithelial-mesenchymal transition.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15107-e15107
Author(s):  
Wan He ◽  
Han Wu ◽  
Dongcheng Liu ◽  
Wenwen Li ◽  
Ruilian Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Lines ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Cells ◽  
Cancer Tissues

e15107 Background: Our previous studies revealed the increased expression of Jagged 2 (JAG2) in most intestinal cancer tissues. In colon cancer cell lines, JAG2 involved in the regulation of migration and invasion without affecting cell proliferation. This study further explored the mechanisms of how JAG2 promotes migration and invasion of colorectal cancer cells. Methods: We analyzed the expression of JAG2 mRNA and protein in normal human colon tissue cells and colorectal cancer cells. The promotive role of JAG2 in migration and invasion was tested by JAG2 siRNA and JAG2 overexpression in various colon cancer cell lines. To understand the mechanisms, we first treated HT29 cells with LY2157299, a TGF-β signaling pathway inhibitor, and Slug siRNA, to identify the cross-talk between JAG2 and EMT pathway. In addition, co-expression status of JAG2 and TGF-β-induced epithelial-mesenchymal transition (EMT) markers was analyzed. Finally, by using siRNA and proteomics technology, co-expressed proteins of JAG2 in colorectal cancer cells were identified. Results: JAG2 was abnormally expressed in colorectal cancer tissues and directly related with clinical stages. Similar to the findings in human tissues, the expression of both JAG2 mRNA and protein was significantly increased in the colorectal cancer cell lines compared with that of normal colorectal cell line CCD18-Co. Interestingly, the promotion of JAG2 in migration and invasion was independent of EMT pathway. Furthermore, we found that the expression of JAG2 was correlated with PRAF2 (PRA1 Domain Family Member 2), a protein involved in the formation of exosome-like vesicles. In the presence of PRAF2, JAG2-rich exosome promoted migration and invasion. JAG2 might regulate the migration and invasion of colon cell through PRAF2. Conclusions: This is the evidence supporting the biological function of JAG2 in migration and invasion through non-EMT-dependent pathways and also the first exploration of the role of PRAF2 in colorectal cancer cells. These findings provide the theoretical basis for potential targeted therapy against JAG2/PRAF2.

scholarly journals Dietary Flavonoids Luteolin and Quercetin Inhibit Migration and Invasion of Squamous Carcinoma through Reduction of Src/Stat3/S100A7 Signaling

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 557 ◽  
Author(s):  
Jhen-Jia Fan ◽  
Wen-Hsien Hsu ◽  
Kuen-Haur Lee ◽  
Ku-Chung Chen ◽  
Cheng-Wei Lin ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Protein Level ◽  
Calcium Binding ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
Dietary Flavonoids

Flavonoids are well-known antioxidants and have shown the ability to prevent tumor formation and recurrence. Especially in dietary flavonoids, they have provided convenience and consistence of intake for long-term prevention of tumor formation. Previous reports suggested that S100 calcium-binding protein A7 (S100A7) might activate epithelial–mesenchymal transition (EMT) signaling and promote the metastasis of tumor cells; however, the regulatory signaling was unclear. In this study, we found that S100A7 was highly expressed in cancer cells and could be reduced by luteolin (Lu) and quercetin (Qu) through Src/Stat3 signaling. We found that the protein levels of S100A7, phosphorylated Src (p-Src), and p-Stat3 were increased in A431-III cells. Flavonoids Lu and Qu reduce protein levels of p-Src, p-Stat3 and S100A7 in A431-III cells. Treatment of A431-III cells with Src inhibitor SU6656 and Stat3 inhibitor S3I-201 also reduced the protein levels of S100A7. Transactivation activity of 5′-upstream regions of S100A7 was activated by Stat3 but was reduced by treatment with Lu, Qu, SU6656 and S3I-201. The treatment also reduced the migratory and invasive abilities of A431-III cells. In a further analysis of EMT markers, the protein level of E-cad increased and that of Twist decreased after treatment with the inhibitors and flavonoids. Overexpression of S100A7 decreased the protein level of E-cad and increased the Twist level, whereas knockdown of S100A7 had the opposite effects. Treatment with S3I-201, Lu and Qu, compared to the control, were found to decrease metastasis of tumor cells in zebrafish larvae. These results suggest that Lu and Qu may inhibit Src/Stat3/S100A7 signaling to reduce tumorigenesis of cancer cells.

scholarly journals Breast Carcinoma: From Initial Tumor Cell Detachment to Settlement at Secondary Sites

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Catharina Melzer ◽  
Juliane von der Ohe ◽  
Ralf Hass
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Surrounding Tissue ◽  
Migration And Invasion ◽  
Cell Detachment ◽  
Primary Tumor Site ◽  
Mesenchymal Transition ◽  
Functional Changes

Metastasis represents a multistep cascade of cancer cell alterations accompanied by structural and functional changes within the tumor microenvironment which may involve the induction of a retrodifferentiation program. Major steps in metastatic developments include (A) cell detachment from the primary tumor site involving epithelial-mesenchymal transition (EMT), (B) migration and invasion into surrounding tissue, (C) transendothelial intravasation into the vasculature of blood and/or lymphatic vessels as circulating tumor cells (CTCs), (D) dissemination to distant organs, and (E) extravasation of CTCs to secondary sites as disseminated tumor cells (DTCs). This article highlights some aspects of the metastatic cascade with a focus on breast cancer cells. Metastatic steps critically depend on the capability of cancer cells to adapt to distant tissues and the corresponding new microenvironment. As a consequence, increasing plasticity and developmental changes paralleled by acquisition of new cancer cell functionalities challenge a successful therapeutic approach.

scholarly journals Targeting a moonlighting function of aldolase induces apoptosis in cancer cells

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Agnieszka Gizak ◽  
Janusz Wiśniewski ◽  
Paul Heron ◽  
Piotr Mamczur ◽  
Jurgen Sygusch ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cellular Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Atp Synthesis ◽  
Pharmacological Action ◽  
Cancer Therapies ◽  
Mesenchymal Transition ◽  
Catalytic Function

Abstract Muscle fructose-1,6-bisphosphate aldolase (ALDOA) is among the most abundant glycolytic enzymes in all cancer cells. Here, we show that the enzyme plays a previously unknown and critical role in a cancer cell survival. Simultaneous inhibition of ALDOA activity and interaction with F-actin cytoskeleton using ALDOA slow-binding inhibitor UM0112176 leads to a rapid cofilin-dependent loss of F-actin stress fibers which is associated with elevated ROS production, inhibition of ATP synthesis, increase in calcium levels, caspase activation and arrested cellular proliferation. These effects can be reproduced by silencing of ALDOA. The mechanism of pharmacological action is, however, independent of the catalytic function of the enzyme, specific to cancer cells, and is most deleterious to cells undergoing the epithelial–mesenchymal transition, a process facilitating cancer cell invasion. Our results demonstrate that the overabundance of ALDOA in cancer cells is associated with its moonlighting rather than catalytic functions. This may have significant implications for development of novel broad-based anti-cancer therapies.

scholarly journals LincHOXA10 Facilitates Colorectal Cancer Development By Regulating HOXA10-Mediated Epithelial-Mesenchymal Transtion

2020 ◽  
Author(s):  
Huifang Zhu ◽  
Yongzhen Li ◽  
Yinghui Zhang ◽  
Zheying Zhang ◽  
Yongxia Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Mesenchymal Transition

Abstract Background: Long non-coding RNAs (lncRNAs) have been reported to play an important role in tumorigenesis and metastasis of human colorectal cancer (CRC). However, the specific role of LincHOXA10 in CRC remains unknown.Methods: The expression of LincHOXA10 and HOXA10 in CRC cells and tissue samples was measured by quantitative reverse transcription PCR (qRT-PCR). The protein expression of HOXA10, E-cadherin, N-cadherin, Vinmentin, p-smad2 and p-smad3 was assessed by Western blotting or immunofluorescence staining. Cell proliferation, migration, and invasion were assessed by the MTT and transwell assays. Tumor growth in vivo was carried out by subcutaneous tumor formation in nude mice.Results: In the present study, we found that LincHOXA10 expression was significantly higher in human CRC tissues than the paired normal tissues. In fact, LincHOXA10 level correlated with the CRC tumor sizes and lymphatic metastasis. In cultured CRC cells, knockdown of LincHOXA10 inhibited cell proliferation, migration and invasion. LincHOXA10 deficiency also attenuated CRC tumor growth in vivo. Mechanistically, LincHOXA10 interacted with HOXA10 and regulated its expression. HOXA10 levels were interrelated to the LincHOXA10 level in CRC cells. Functionally, HOXA10 was essential for TGF-β1/SMADs-induced epithelial -mesenchymal transition of CRC cells, and HOXA10 played a critical role in mediating the function of LincHOXA10. Importantly, HOXA10 expression was significantly up-regulated in human CRC tissues.Conclusions: LincHOXA10 facilitates CRC development and metastasis via regulating HOXA10-mediated epithelial-mesenchymal transition of CRC cells.

scholarly journals Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 558
Author(s):  
Jin Kyung Seok ◽  
Eun-Hee Hong ◽  
Gabsik Yang ◽  
Hye Eun Lee ◽  
Sin-Eun Kim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Oxidized Phospholipids ◽  
Mcf7 Cells ◽  
Mesenchymal Transition ◽  
Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

scholarly journals MBP-1 Suppresses Growth and Metastasis of Gastric Cancer Cells through COX-2

2009 ◽  
Vol 20 (24) ◽  
pp. 5127-5137 ◽  
Author(s):  
Kai-Wen Hsu ◽  
Rong-Hong Hsieh ◽  
Chew-Wun Wu ◽  
Chin-Wen Chi ◽  
Yan-Hwa Wu Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Suppressive Effect ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Mesenchymal Transition ◽  
Cox 2

The c-Myc promoter binding protein 1 (MBP-1) is a transcriptional suppressor of c-myc expression and involved in control of tumorigenesis. Gastric cancer is one of the most frequent neoplasms and lethal malignancies worldwide. So far, the regulatory mechanism of its aggressiveness has not been clearly characterized. Here we studied roles of MBP-1 in gastric cancer progression. We found that cell proliferation was inhibited by MBP-1 overexpression in human stomach adenocarcinoma SC-M1 cells. Colony formation, migration, and invasion abilities of SC-M1 cells were suppressed by MBP-1 overexpression but promoted by MBP-1 knockdown. Furthermore, the xenografted tumor growth of SC-M1 cells was suppressed by MBP-1 overexpression. Metastasis in lungs of mice was inhibited by MBP-1 after tail vein injection with SC-M1 cells. MBP-1 also suppressed epithelial-mesenchymal transition in SC-M1 cells. Additionally, MBP-1 bound on cyclooxygenase 2 (COX-2) promoter and downregulated COX-2 expression. The MBP-1-suppressed tumor progression in SC-M1 cells were through inhibition of COX-2 expression. MBP-1 also exerted a suppressive effect on tumor progression of other gastric cancer cells such as AGS and NUGC-3 cells. Taken together, these results suggest that MBP-1–suppressed COX-2 expression plays an important role in the inhibition of growth and progression of gastric cancer.

The Impacts of Bone Marrow Mesenchymal Stem Cells (BMSCs)-Derived Periostin on Epithelial-Mesenchymal Transition (EMT) of Cervical Cancer Cells

2022 ◽  
Vol 12 (4) ◽  
pp. 820-826
Author(s):  
Chengyong Wu ◽  
Weifeng Wei ◽  
Jing Li ◽  
Shenglin Peng
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Signal Transduction Pathway ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Essential Components ◽  
Cervical Cancer Cells ◽  
E Cadherin

Epithelial-mesenchymal transition (EMT) is closely related to the migrating and invading behaviors of cells. Periostin is one of the essential components in the extracellular matrix and can induce EMT of cells and their sequential metastasis. But its underlying mechanism is unclear. The Hela and BMSC cell lines were assigned into Periostin-mimic group, Periostin-Inhibitor group and Periostin-NC group followed by analysis of cell migration and invasion, expression of E-Cadherin, Vimentin, β-Catenin, Snail, MMP-2, MMP-9, PTEN, and p-PTEN. Cells in Periostin-mimic group exhibited lowest migration, least number of invaded cells, as well as lowest levels of Vimentin, β-Catenin, Snail, MMP-2, MMP-9, p-PTEN, Akt, p-Akt, p-GSK-3β, p-PDK1 and p-cRcf, along with highest levels of E-cadherin and PTEN. Moreover, cells in Periostin-NC group had intermediate levels of these above indicators, while, the Periostin-Inhibitor group exhibited the highest migration rate, the most number of invaded cells, and the highest levels of these proteins (P < 0.05). In conclusion, BMSCs-derived Periostin can influence the EMT of cervical cancer cells possibly through restraining the activity of the PI3K/AKT signal transduction pathway, indicating that Periostin might be a target of chemotherapy in clinics for the treatment of cervical cancer.

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