Targeting a moonlighting function of aldolase induces apoptosis in cancer cells

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.

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Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

Mediators of Inflammation ◽

10.1155/2021/6655417 ◽

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.

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The effect of hepatic stellate cells on hepatocellular carcinoma progression.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.265 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 265-265

Author(s):

Shuichi Iwahashi ◽

Mitsuo Shimada ◽

Yuji Morine ◽

Satoru Imura ◽

Tetsuya Ikemoto ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Stellate Cells ◽

Stem Cell Marker ◽

Cell Marker ◽

Migration Ability ◽

Mesenchymal Transition ◽

And Migration ◽

E Cadherin

265 Background: The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Some manuscripts mentioned that activated HSCs predicted prognoses of hepatocellular carcinoma. The aim of this study is to investigate the effect of HSCs and the role of IL-6 / Stat3 pathway on HCC progression. Methods: HCC cells (Hep G2 and Huh 7) were co-cultured with HSC (LX2 and Li90). The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44), TGF-b and p-STAT3 of cancer cells were evaluated. Then the IL-6 neutralization was performed during HCC cells and HSCs co-culture. The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44) and p-STAT3 of cancer cells were evaluated. Results: Co-culture with hepatic stellate cell increased cancer cell viability and migration ability. The expression of E-cadherin, EpCAM and CD44 of cancer cells also increased after co-culture with HSCs. The IL-6 expression and secretion of HSCs were elevated by cancer cell stimulation. The over-expressed IL-6 activated STAT3 of cancer cell showed as the level of phosphorylated STAT3 increased. Neutralized IL-6 during co-culture significantly decrease the viability and migration ability of cancer cells. Also, the expression of E-cadherin, EpCAM and CD44 of cancer cells decreased. Conclusions: HSCs might promote HCC progression through IL-6 / STAT3 pathway.

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Ginsenoside Rg3 Suppresses Epithelial-Mesenchymal Transition via Downregulating Notch-Hes1 Signaling in Colon Cancer Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x21500129 ◽

2020 ◽

pp. 1-19

Author(s):

Xiao Li ◽

Wei Liu ◽

Chong Geng ◽

Tingting Li ◽

Yanni Li ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Colon Cancer Cell ◽

Colon Cancer Cells ◽

Ginsenoside Rg3 ◽

Invasion And Metastasis ◽

Mesenchymal Transition ◽

E Cadherin

Invasion and metastasis are the major causes leading to the high mortality of colon cancer. Ginsenoside Rg3 (Rg3), as a bioactive ginseng compound, is suggested to possess antimetastasis effects in colon cancer. However, the underlying molecular mechanisms remain unclear. In this study, we reported that Rg3 could effectively inhibit colon cancer cell invasion and metastasis through in vivo and in vitro studies. In addition, Rg3 suppressed the epithelial–mesenchymal transition (EMT) of HCT15 cells and SW48 cells evidenced by detecting EMT related markers E-cadherin, vimentin, and snail expression. Furthermore, inhibition of Notch signaling by LY411,575 or specific Hes1 siRNA obviously repressed colon cancer cell migration and metastasis, and induced increase in E-cadherin and decrease in vimentin and snail. Meanwhile, the expression of NICD and Hes1 was obviously decreased in the presence of Rg3. However, Rg3 failed to suppress EMT in Hes1 overexpressed colon cancer cells. In particular, Rg3 significantly reversed IL-6-induced EMT promotion and blocked IL-6- induced NICD and Hes1 upregulations. Overall, these findings suggested that Rg3 could inhibit colon cancer migration and metastasis via suppressing Notch-Hes1-EMT signaling.

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MBD1 promotes the malignant behavior of gallbladder cancer cells and induces chemotherapeutic resistance to gemcitabine

Cancer Cell International ◽

10.1186/s12935-019-0948-1 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Liu Wensheng ◽

Zhang Bo ◽

Hu Qiangsheng ◽

Xu Wenyan ◽

Ji Shunrong ◽

...

Keyword(s):

Protein Expression ◽

Cell Viability ◽

Gallbladder Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Tumor Development ◽

Human Gallbladder ◽

Mesenchymal Transition ◽

Cancer Tissues

Abstract Background Methyl-CpG binding domain protein 1 (MBD1), which couples DNA methylation to transcriptional repression, has been implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell cycle progression and development. It has also been proven that MBD1 is involved in tumor development and progression. However, whether MBD1 is involved in tumorigenesis, especially in gallbladder cancer, is totally unknown. Methods Human GBC-SD and SGC996 cells were used to perform experiments. Invasion, wound healing and colony formation assays were performed to evaluate cell viability. A CCK-8 assay was performed to assess gallbladder cancer cell viability after gemcitabine treatment. Western blot analysis was used to evaluate changes in protein expression. Human gallbladder cancer tissues and adjacent nontumor tissues were subjected to immunohistochemical staining to detect protein expression. Results We found that MBD1 expression was significantly upregulated in gallbladder cancer tissues compared with that in surrounding normal tissues according to immunohistochemical analysis of 84 surgically resected gallbladder cancer specimens. These data also indicated that higher MBD1 expression was correlated with lymph node metastasis and poor survival in gallbladder cancer patients. Overexpression and deletion in vitro validated MBD1 as a potent oncogene promoting malignant behaviors in gallbladder cancer cells, including invasion, proliferation and migration, as well as epithelial–mesenchymal transition. Studies have demonstrated that epithelial–mesenchymal transition is common in gallbladder cancer, and it is well known that drug resistance and epithelial–mesenchymal transition are very closely correlated. Herein, our data show that targeting MBD1 restored gallbladder cancer cell sensitivity to gemcitabine chemotherapy. Conclusions Taken together, the results of our study revealed a novel function of MBD1 in gallbladder cancer tumor development and progression through participation in the gallbladder cancer epithelial–mesenchymal transition program, which is involved in resistance to gemcitabine chemotherapy. Thus, MBD1 may be a potential therapeutic target for gallbladder cancer.

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The Effect of Dihydroartemisinin on the Malignancy and Epithelial-Mesenchymal Transition of Gastric Cancer Cells

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190611124644 ◽

2019 ◽

Vol 20 (9) ◽

pp. 719-726 ◽

Cited By ~ 1

Author(s):

Nan Li ◽

Suyun Zhang ◽

Qiong Luo ◽

Fang Yuan ◽

Rui Feng ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Gastric Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Gastric Cancer Cell Line ◽

Cancer Cell Line ◽

Gastric Cancer Cells ◽

Mesenchymal Transition ◽

Expression Levels

Objective: This study aimed to observe the effects of dihydroartemisinin (DHA) on the proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) of the human gastric cancer cell line SGC7901 cultured in vitro. Methods: We applied varying concentrations of DHA to SGC7901 cells. Cell proliferation was measured using the cell counting kit-8 (CCK-8). Flow cytometry, Transwell invasion assay, and cell scratch assay were used to investigate the cells’ apoptosis, invasion, and migration. Western blot was used to assess the expression levels of EMT markers E-cadhein and Vimentin, protein kinases Akt and phosphorylated AKT (p-AKT), and the cell transcription factor Snail. Results: DHA can effectively inhibit the malignant proliferation of gastric cancer cells in a time- and dose-dependent manner. In this study, with longer incubation times and increased drug concentrations, the antiproliferation effect of DHA on SGC7901 cells increased gradually (P<0.05). In addition, with the increase of drug concentration, the expression levels of E-cadhein, an epithelial-mesenchymal transition marker, remarkably increased, whereas the protein expression levels of the mesenchymal markers Vimentin, Akt, p-Akt, and Snail significantly decreased (P<0.05). Conclusion: DHA can effectively inhibit the proliferation, invasion, and metastasis of the gastric cancer cell line SGC7901 and induce cancer cell apoptosis. DHA can also downregulate PI3K/AKT and Snail activities and inhibit the epithelial-mesenchymal transition of gastric cancer cells. The potential anticancer effects of DHA deserve further investigation.

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Effect of neuropilin-2 expression on TGF-β1-epithelial-mesenchymal transition in colorectal cancer cells.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.414 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 414-414

Author(s):

C. Grandclement ◽

R. Bedel ◽

B. Kantelip ◽

E. Viel ◽

J. Remy Martin ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Human Colon ◽

Mesenchymal Transition ◽

Colorectal Cancer Cells ◽

Tgf Β1

414 Background: Initially characterized as neuronal receptors, Neuropilins (NRPs) were also found to be expressed in endothelial cells and subsequently were shown to play a role in the development of the vascular system. NRP family consists of two genes, neuropilin-1 (NRP1) and neuropilin-2 (NRP2).The multiple functions of NRPs were recently highlighted by the identification of NRP role in oncogenesis. In this study, we first confirmed the role of NRP2 in tumor progression. We also extended the understanding of NRP2 oncogenic functions by investigating the ability of NRP2 to orchestrate epithelial-mesenchymal transition (EMT) in colorectal cancer cells. Methods: We have generated human colon cancer cell lines transfected with NRP2 transgene or siRNA to investigate NRP2 involvement in EMT. First, the oncogenic functions of NRP2 were studied in vitro by MTT, soft agar, invasion assays and in vivo using xenografts experiments. Ability of NRP2 to orchestrate EMT was then investigated by flow cytometry, immunohistochemical (IHC) staining, western-blotting and quantitative real-time PCR. Results: IHC staining revealed that NRP2 is expressed in human colon and breast carcinomas while it is not expressed in healthy tissues. Then, we confirmed that NRP2 increases tumor proliferation, colony formation, invasion and xenograft formation. Moreover, NRP2-expressing cells displayed an immunohistochemical phenotype of EMT characterized by the loss of E-Cadherin and an increase of vimentin. Furthermore, NRP2 expression promotes transforming-growth factor-β1 (TGF- β1) signaling, leading to an increased phosphorylation of the Smad2/3 complex in colorectal cancer cell lines. Specific inhibition of NRP2 using siRNA or treatment with specific TGFβRI kinase inhibitors prevented this phosphorylation and the EMT, suggesting that NRP2 cooperates with TGFRI to promote EMT in colorectal carcinoma. Conclusions: Our findings have reinforced the essential role of NRP2 in cancer progression and demonstrated that NRP2 expression confers to tumor cell lines the hallmarks of EMT. Moreover, in the current work, we present evidence for the therapeutic value of NRP2 targeting. No significant financial relationships to disclose.

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

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15107 ◽

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.

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MiR-543 Promotes Proliferation and Epithelial-Mesenchymal Transition in Prostate Cancer via Targeting RKIP

Cellular Physiology and Biochemistry ◽

10.1159/000464120 ◽

2017 ◽

Vol 41 (3) ◽

pp. 1135-1146 ◽

Cited By ~ 36

Author(s):

Yang Du ◽

Xiu-heng Liu ◽

Heng-cheng Zhu ◽

Lei Wang ◽

Jin-zhuo Ning ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

In Vivo Studies ◽

Mesenchymal Transition ◽

Proliferation And Metastasis

Background/Aims: MicroRNAs (miRNAs, miRs) have emerged as important post-transcriptional regulators in various cancers. miR-543 has been reported to play critical roles in hepatocellular carcinoma and colorectal cancer, however, the role of miR-543 in the pathogenesis of prostate cancer has not been fully understood. Methods: Expression of miR-543 and Raf Kinase Inhibitory Protein (RKIP) in clinical prostate cancer specimens, two prostate cancer cell lines, namely LNCAP and C4-2B, were determined. The effects of miR-543 on proliferation and metastasis of tumor cells were also investigated with both in vitro and in vivo studies. Results: miR-543 was found to be negatively correlated with RKIP expression in clinical tumor samples and was significantly upregulated in metastatic prostate cancer cell line C4-2B compared with parental LNCAP cells. Further studies identified RKIP as a direct target of miR-543. Overexpression of miR-543 downregulated RKIP expression and promoted the proliferation and metastasis of cancer cells, whereas knockdown of miR-543 increased expression of RKIP and suppressed the proliferation and metastasis of cancer cells in vitro and in vivo. Conclusion: Our study demonstrates that miR-543 promotes the proliferation and metastasis of prostate cancer via targeting RKIP.

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Free-Radical Polymer Science Structural Cancer Model: A Review

Scientifica ◽

10.1155/2013/143589 ◽

2013 ◽

Vol 2013 ◽

pp. 1-17 ◽

Cited By ~ 1

Author(s):

Richard C. Petersen

Keyword(s):

Free Radical ◽

Cancer Cells ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Cell Movement ◽

Low Ph ◽

Chain Growth ◽

Polymer Science ◽

Mesenchymal Transition ◽

Hypoxic Conditions

Polymer free-radical lipid alkene chain-growth biological models particularly for hypoxic cellular mitochondrial metabolic waste can be used to better understand abnormal cancer cell morphology and invasive metastasis. Without oxygen as the final electron acceptor for mitochondrial energy synthesis, protons cannot combine to form water and instead mitochondria produce free radicals and acid during hypoxia. Nonuniform bond-length shrinkage of membranes related to erratic free-radical covalent crosslinking can explain cancer-cell pleomorphism with epithelial-mesenchymal transition for irregular membrane borders that “ruffle” and warp over stiff underlying actin fibers. Further, mitochondrial hypoxic conditions produce acid that can cause molecular degradation. Subsequent low pH-activated enzymes then provide paths for invasive cell movement through tissue and eventually blood-born metastasis. Although free-radical crosslinking creates irregularly shaped membranes with structural actin-polymerized fiber extensions as filopodia and lamellipodia, due to rapid cell division the overall cell modulus (approximately stiffness) is lower than normal cells. When combined with low pH-activated enzymes and lower modulus cells, smaller cancer stem cells subsequently have a large advantage to follow molecular destructive pathways and leave the central tumor. In addition, forward structural spike-like lamellipodia protrusions can leverage to force lower-modulus cancer cells through narrow openings. By squeezing and deforming even smaller to allow for easier movement through difficult passageways, cancer cells can travel into adjacent tissues or possibly metastasize through the blood to new tissue.

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Yeast-Derived Recombinant Avenanthramides Inhibit Proliferation, Migration and Epithelial Mesenchymal Transition of Colon Cancer Cells

Nutrients ◽

10.3390/nu10091159 ◽

2018 ◽

Vol 10 (9) ◽

pp. 1159 ◽

Cited By ~ 5

Author(s):

Federica Finetti ◽

Andrea Moglia ◽

Irene Schiavo ◽

Sandra Donnini ◽

Giovanni Berta ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Antioxidant Properties ◽

Colon Cancer Cells ◽

Mesenchymal Transition ◽

Molecular Features ◽

Hydroxyanthranilic Acid ◽

The Impact

Avenanthramides (Avns), polyphenols found exclusively in oats, are emerging as promising therapeutic candidates for the treatment of several human diseases, including colon cancer. By engineering a Saccharomyces cerevisiae strain, we previously produced two novel phenolic compounds, N-(E)-p-coumaroyl-3-hydroxyanthranilic acid (Yeast avenanthramide I, YAvnI) and N-(E)-caffeoyl-3-hydroxyanthranilic acid (Yeast avenanthramide II, YAvnII), which are endowed with a structural similarity to bioactive oat avenanthramides and stronger antioxidant properties. In this study, we evaluated the ability of these yeast-derived recombinant avenanthramides to inhibit major hallmarks of colon cancer cells, including sustained proliferation, migration and epithelial-mesenchymal transition (EMT). Using the human colon adenocarcinoma cell line HT29, we compared the impact of YAvns and natural Avns, including Avn-A and Avn-C, on colon cancer cells by performing MTT, clonogenic, adhesion, migration, and anchorage-independent growth assays, and analyzing the expression of EMT markers. We found that both YAvns and Avns were able to inhibit colon cancer cell growth by increasing the expression of p21, p27 and p53 proteins. However, YAvns resulted more effective than natural compounds in inhibiting cancer cell migration and reverting major molecular features of the EMT process, including the down-regulation of E-cadherin mRNA and protein levels.

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