scholarly journals Physiological Roles of ERM Proteins and Transcriptional Regulators in Supporting Membrane Expression of Efflux Transporters as Factors of Drug Resistance in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3352
Author(s):  
Takuo Ogihara ◽  
Kenta Mizoi ◽  
Hiroki Kamioka ◽  
Kentaro Yano
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Transcriptional Regulators ◽  
Scaffold Proteins ◽  
Efflux Transporters ◽  
Cancer Resistance ◽  
Erm Proteins ◽  
Mesenchymal Transition ◽  
The Relationship

One factor contributing to the malignancy of cancer cells is the acquisition of drug resistance during chemotherapy via increased expression of efflux transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP). These transporters operate at the cell membrane, and are anchored in place by the scaffold proteins ezrin (Ezr), radixin (Rdx), and moesin (Msn) (ERM proteins), which regulate their functional activity. The identity of the regulatory scaffold protein(s) differs depending upon the transporter, and also upon the tissue in which it is expressed, even for the same transporter. Another factor contributing to malignancy is metastatic ability. Epithelial–mesenchymal transition (EMT) is the first step in the conversion of primary epithelial cells into mesenchymal cells that can be transported to other organs via the blood. The SNAI family, a transcriptional regulators triggers EMT, and SNAI expression is used is an indicator of malignancy. Furthermore, EMT has been suggested to be involved in drug resistance, since drug excretion from cancer cells is promoted during EMT. We showed recently that ERM proteins are induced by a member of the SNAI family, Snail. Here, we first review recent progress in research on the relationship between efflux transporters and scaffold proteins, including the question of tissue specificity. In the second part, we review the relationship between ERM scaffold proteins and the transcriptional regulatory factors that induce their expression.

scholarly journals Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

2020 ◽  
Vol 21 (11) ◽  
pp. 4002 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Ali Zarrabi ◽  
Kiavash Hushmandi ◽  
Mahshad Kalantari ◽  
Reza Mohammadinejad ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Nuclear Factor Κb ◽  
Molecular Pathways ◽  
Cancer Resistance ◽  
Mesenchymal Transition ◽  
The Impact

Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP chemotherapy has been extensively observed. Among various reported mechanism(s), the epithelial–mesenchymal transition (EMT) process can significantly contribute to chemoresistance by converting the motionless epithelial cells into mobile mesenchymal cells and altering cell–cell adhesion as well as the cellular extracellular matrix, leading to invasion of tumor cells. By analyzing the impact of the different molecular pathways such as microRNAs, long non-coding RNAs, nuclear factor-κB (NF-ĸB), phosphoinositide 3-kinase-related protein kinase (PI3K)/Akt, mammalian target rapamycin (mTOR), and Wnt, which play an important role in resistance exhibited to CP therapy, we first give an introduction about the EMT mechanism and its role in drug resistance. We then focus specifically on the molecular pathways involved in drug resistance and the pharmacological strategies that can be used to mitigate this resistance. Overall, we highlight the various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure.

scholarly journals Recent Advances in Understanding the Mechanisms of Elemene in Reversing Drug Resistance in Tumor Cells: A Review

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5792
Author(s):  
Tiantian Tan ◽  
Jie Li ◽  
Ruhua Luo ◽  
Rongrong Wang ◽  
Liyan Yin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Tumor Resistance ◽  
Mesenchymal Transition ◽  
Life Threatening ◽  
The Common ◽  
Abcb1 Transporter

Malignant tumors are life-threatening, and chemotherapy is one of the common treatment methods. However, there are often many factors that contribute to the failure of chemotherapy. The multidrug resistance of cancer cells during chemotherapy has been reported, since tumor cells’ sensitivity decreases over time. To overcome these problems, extensive studies have been conducted to reverse drug resistance in tumor cells. Elemene, an extract of the natural drug Curcuma wenyujin, has been found to reverse drug resistance and sensitize cancer cells to chemotherapy. Mechanisms by which elemene reverses tumor resistance include inhibiting the efflux of ATP binding cassette subfamily B member 1(ABCB1) transporter, reducing the transmission of exosomes, inducing apoptosis and autophagy, regulating the expression of key genes and proteins in various signaling pathways, blocking the cell cycle, inhibiting stemness, epithelial–mesenchymal transition, and so on. In this paper, the mechanisms of elemene’s reversal of drug resistance are comprehensively reviewed.

scholarly journals New Advances in the Research of Resistance to Neoadjuvant Chemotherapy in Breast Cancer

2021 ◽  
Vol 22 (17) ◽  
pp. 9644
Author(s):  
Junsha An ◽  
Cheng Peng ◽  
Hailin Tang ◽  
Xiuxiu Liu ◽  
Fu Peng
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Drug Targets ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Treatment Plan ◽  
Mesenchymal Transition ◽  
Chemotherapy Drugs

Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of medicine today, the clinical application of neoadjuvant chemotherapy has brought new hope to the treatment of breast cancer. Although the efficacy of neoadjuvant chemotherapy has been confirmed, drug resistance is one of the main reasons for its treatment failure, contributing to the difficulty in the treatment of breast cancer. This article focuses on multiple mechanisms of action and expounds a series of recent research advances that mediate drug resistance in breast cancer cells. Drug metabolizing enzymes can mediate a catalytic reaction to inactivate chemotherapeutic drugs and develop drug resistance. The drug efflux system can reduce the drug concentration in breast cancer cells. The combination of glutathione detoxification system and platinum drugs can cause breast cancer cells to be insensitive to drugs. Changes in drug targets have led to poorer efficacy of HER2 receptor inhibitors. Moreover, autophagy, epithelial–mesenchymal transition, and tumor microenvironment can all contribute to the development of resistance in breast cancer cells. Based on the relevant research on the existing drug resistance mechanism, the current treatment plan for reversing the resistance of breast cancer to neoadjuvant chemotherapy is explored, and the potential drug targets are analyzed, aiming to provide a new idea and strategy to reverse the resistance of neoadjuvant chemotherapy drugs in breast cancer.

Quest of EMT and CSC

2019 ◽  
Author(s):  
Shihori Tanabe
Keyword(s):  
Drug Resistance ◽  
Stem Cell ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Therapeutics ◽  
Cancer Drug ◽  
Phenotypic Change ◽  
Mesenchymal Transition ◽  
Cancer Drug Resistance ◽  
The Relationship

Epithelial-mesenchymal transition (EMT), an important phenotypic change from epithelial to mesenchymal like cells, has the increasing impact for cancer progression in terms of the involvement in cancer stem cell (CSC). The EMT-featured cells and CSCs are important factors for the acquisition of cancer drug resistance. The understanding of EMT program activation is important for targeting CSCs in cancer therapy. The relationship between EMT and CSC in cancer therapeutics is focused in the editorial.

scholarly journals TLR-mediated miR-125b-5p downregulation enhances CD248-induced metastasis and drug resistance in colorectal cancer cells

2019 ◽  
Author(s):  
GA-BIN PARK ◽  
Daejin Kim
Keyword(s):  
Colon Cancer ◽  
Drug Resistance ◽  
Gene Silencing ◽  
Cancer Cells ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Drug Resistant ◽  
Colon Cancer Cells ◽  
Mesenchymal Transition ◽  
Migratory Activity

Abstract Background CD248, also called endosialin or tumor endothelial marker-1 (TEM1), is markedly upregulated in almost all cancers, including colon cancers. Changes in microRNA (miRNA) profiles are one of the direct causes of cancer development and progression. In this study, we investigated whether a change in CD248 expression in colon cancer cells could induce drug resistance after chemotherapy, and we explored the relationship between miR-125b-5p levels and CD248 expression in Toll-like receptor (TLR)-modified chemoresistant colon cancer cells. Methods We identified the one of the downregulated miRNAs in drug-resistant HCT8 cells using Affymetrix Genechip miRNA 4.0 array process and validated the expressional change of chemoresistant HCT-116 and HT-29 cells. Interaction between Sp1 and miR-125b-5p was confirmed by miScript target protector assay. To characterize the underlying mechanisms involved in CD248 expression, we adapted the several biological analysis techniques, including RNA-binding Protein Immunoprecipitation (RIP), migration analysis, real-Time PCR, western blot analysis, and gene silencing using siRNA. Results TLR2/6 and TLR5 upregulation in drug-resistant colon cancer cells contributed to miR-125b-5p downregulation and Sp1-mediated CD248 upregulation via NF-κB activation. Exposure to specific TLR2/6 or TLR5 ligands enhanced the expression of mesenchymal markers as well as the migratory activity of oxaliplatin (Ox)- or 5-fluorouracil (5-Fu)-resistant colon cancer cells. The transfection of a synthetic miR-125b-5p mimic into chemoresistant cells prevented Sp1 and CD248 activation and significantly impaired invasive activity. Furthermore, Sp1 or CD248 gene silencing as well as miR-125b-5p overexpression markedly reversed drug resistance and inhibited epithelial-mesenchymal transition (EMT) in colon cancer cells. Conclusions Taken together, these results suggest that changes in miR-125b-5p levels play an important role in Sp1-mediated CD248 expression and the development of drug resistance in TLR-mutated colon cancer cells.

scholarly journals Correlations of mRNA Levels among Efflux Transporters, Transcriptional Regulators, and Scaffold Proteins in Non-Small-Cell Lung Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Xieyi Zhang ◽  
Wangyang Liu ◽  
Kazue Edaki ◽  
Yuta Nakazawa ◽  
Hiroki Kamioka ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Multidrug Resistance ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Transcriptional Regulators ◽  
Scaffold Proteins ◽  
Lung Cancer Cells ◽  
Efflux Transporters ◽  
Expression Levels ◽  
Mrna Expression Levels

Multidrug resistance (MDR) due to enhanced drug efflux activity of tumor cells can severely impact the efficacy of antitumor therapies. We recently showed that increased activity of the efflux transporter P-glycoprotein (P-gp) associated with activation of Snail transcriptional regulators may be mediated mainly by moesin in lung cancer cells. Here, we aimed to systematically evaluate the relationships among mRNA expression levels of efflux transporters (P-gp, breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2)), scaffold proteins (ezrin (Ezr), radixin (Rdx), and moesin (Msn); ERM proteins), and SNAI family members (Snail, Slug, and Smac) in clinical lung cancer and noncancer samples. We found high correlations between relative (cancer/noncancer) mRNA expression levels of Snail and Msn, Msn and P-gp, Slug and MRP2, and Smuc and BCRP. These findings support our previous conclusion that Snail regulates P-gp activity via Msn and further suggest that Slug and Smuc may contribute to the functional regulation of MRP2 and BCRP, respectively, in lung cancer cells. This trial is registered with UMIN000023923.

1 E-Cadherin knockdown induces cancer stem cell-like phenotype and drug resistance

2021 ◽  
Author(s):  
Anuka Sharma ◽  
Harmandeep Kaur ◽  
Renaissa De ◽  
Radhika Srinivasan ◽  
Arnab Pal ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Stem Cell Marker ◽  
Mesenchymal Transition ◽  
Cytotoxicity Studies ◽  
Cervical Cancer Cells ◽  
E Cadherin

Cervical cancer is one of the leading causes of mortality amongst women in developing countries and therapy resistance is the main reason for its treatment failure. Recent advances suggest that cancer stem cells (CSCs) are critically involved in regulating the chemo resistant behavior of cervical cancer cells. In our study the CSC phenotype cells were isolated and the expression of stem cell marker and epithelial-mesenchymal transition (EMT) associated gene was confirmed by various assays. However, these CSC phenotype cells cannot be cultured for further cytotoxicity studies. So, we tried to establish a CSC model in cervical cancer cells. We performed the siRNA-mediated knockdown of E-cadherin (E-cad) in these cells and studied EMT associated stem cell-like properties in them. We also performed dose dependent cell viability assay using clinically relevant drugs such as cisplatin, cyclopamine and GANT58 to analyze the drug resistant behavior of these cancer cells. We found that E-cad knockdown induces EMT in cervical cancer cells imparting stem-cell like characteristics along with enhanced tumorsphere formation, migration, invasion ability and drug resistance. This is the first study to establish a CSC model in cervical cancer cells by knockdown of E-cad which can be utilized for development of anti-cancer therapies.

scholarly journals Ferritinophagic Flux Activation in CT26 Cells Contributed to EMT Inhibition Induced by a Novel Iron Chelator, DpdtpA

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Yanjie Sun ◽  
Cuiping Li ◽  
Jiankang Feng ◽  
Yongli Li ◽  
Xinbo Zhai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Correlation Analysis ◽  
Driving Force ◽  
Epithelial Mesenchymal Transition ◽  
Iron Chelator ◽  
Iron Chelators ◽  
Ros Production ◽  
Mesenchymal Transition ◽  
New Finding ◽  
The Relationship

Epithelial-mesenchymal transition (EMT) contributes to metastasis and drug resistance; inhibition of EMT may attenuate metastasis and drug resistance. It has been demonstrated that ferritinophagy involves the process of many diseases; however, the relationship between EMT and ferritinophagy was not fully established. Some iron chelators show the ability to inhibit EMT, but whether ferritinophagy plays a role in EMT is largely unknown. To this end, we investigated the effect of a novel iron chelator, DpdtpA (2,2′-di-pyridylketone dithiocarbamate propionic acid), on EMT in the CT26 cell line. The DpdtpA displayed excellent antitumor (IC50=1.5±0.2 μM), leading to ROS production and apoptosis occurrence. Moreover, the ROS production correlated with ferritin degradation. The upregulation of LC3-II and NCOA4 from immunofluorescence and Western blotting analysis revealed that the occurrence of ferritinophagy contributed to ROS production. Furthermore, DpdtpA could induce an alteration both in morphology and in epithelial-mesenchymal markers, displaying significant EMT inhibition. The correlation analysis revealed that DpdtpA-induced ferritinophagy contributed to the EMT inhibition, implying that NCOA4 involved EMT process, which was firstly reported. To reinforce this concept, the ferritinophagic flux (NCOA4/ferritin) in either treated by TGF-β1 or combined with DpdtpA was determined. The results indicated that activating ferritinophagic flux would enhance ROS production which accordingly suppressed EMT or implementing the EMT suppression seemed to be through “fighting fire with fire” strategy. Taken together, our data demonstrated that ferritinophagic flux was a dominating driving force in EMT proceeding, and the new finding definitely will enrich our knowledge of ferritinophagy in EMT process.

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