scholarly journals The Effect of Tau and Taxol on Polymerization of MCF7 Microtubules In Vitro

2022 ◽  
Vol 23 (2) ◽  
pp. 677
Author(s):  
Mitra Shojania Feizabadi ◽  
Venise Jan Castillon
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Tau Protein ◽  
Molecular Motors ◽  
Resistance Mechanism ◽  
Underlying Mechanism ◽  
Beta Tubulin ◽  
Associated Proteins

Overexpression of Tau protein in breast cancer cells is identified as an indicator for potential resistance to taxane-based therapy. As reported findings have been obtained mostly from clinical studies, the undetermined underlying mechanism of such drug resistance needs to be thoroughly explored through comprehensive in vitro evaluations. Tau and Taxol bind to the beta tubulin site in microtubules’ structure. This is of particular interest in breast cancer, as microtubules of these cancer cells are structurally distinct from some other microtubules, such as neuronal microtubules, due to their unique beta tubulin isotype distribution. The observed changes in the in vitro polymerization of breast cancer microtubules, and the different function of some molecular motors along them, leave open the possibility that the drug resistance mechanism can potentially be associated with different responses of these microtubules to Tau and Taxol. We carried out a series of parallel experiments to allow comparison of the in vitro dual effect of Tau and Taxol on the polymerization of MCF7 microtubules. We observed a concentration-dependent demotion-like alteration in the self-polymerization kinetics of Tau-induced MCF7 microtubules. In contrast, microtubules polymerized under the simultaneous effects of Tau and Taxol showed promoted assembly as compared with those observed in Tau-induced microtubules. The analysis of our data obtained from the length of MCF7 microtubules polymerized under the interaction with Tau and Taxol in vitro suggests that the phenomenon known as drug resistance in microtubule-targeted drugs such as Taxol may not be directly linked to the different responses of microtubules to the drug. The effect of the drug may be mitigated due to the simultaneous interactions with other microtubule-associated proteins such as Tau protein. The observed regulatory effect of Tau and Taxol on the polymerization of breast cancer microtubules in vitro points to additional evidence for the possible role of tubulin isotypes in microtubules’ functions.

PEAK1 promotes invasion and metastasis and confers drug resistance in breast cancer

2021 ◽  
Author(s):  
xingang wang ◽  
YAN ZHENG ◽  
YU WANG
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Multi Drug Resistance ◽  
Cancer Tissues

Abstract Background and AimsPseudopodium-enriched atypical kinase 1 (PEAK1) has reported to be upregulated in human malignancies and related with poor prognosis. Enhanced PEAK1 expression facilitates tumor cell survival, invasion, metastasis and chemoresistance. However, the role of PEAK1 in breast cancer is not clear. Here, we investigated the PEAK1 expression in breast cancer and analyzed its relation with clinicopathological status and chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated the role of PEAK1 on breast cancer cells in vitro and in vivo. MethodsImmunohistochemistry (IHC) was performed in 112 surgical resected breast cancer tissues. The associations between clinicopathological status, multi-drug resistance and PEAK1 expression were determined. Effect of PEAK1 overexpression or down-expression on proliferation, colony formation, invasion, migration, metastasis and Doxorubicin sensitivity in the MCF-7 cells in vitro and in vivo was detected. ResultsPEAK1 was overexpressed in breast cancer tissues and NAC -resistant breast cancer tissues. High PEAK1 expression was related with tumor size, high tumor grade, T stage, LN metastasis, recurrence, Ki-67 expression, Her-2 expression and multi-drug resistance. Targeting PEAK1 inhibited cell growth, invasion, metastasis and reversed chemoresistance to Doxorubicin in breast cancer cells in vitro and in vivo. ConclusionHigh PEAK1 expression was associated with invasion, metastasis and chemoresistance of breast cancers. Furthermore, targeting PEAK1 could inhibit cell growth and metastasis, and reverse chemoresistance in breast cancer cells, which provides an effective treatment strategies for breast cancer.

The underlying mechanism contributing to P-gp over-expression and drug resistance in the MCF-7 breast cancer cells induced by adriamycin.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12028-e12028
Author(s):  
Guangji Wang ◽  
Jiye Aa ◽  
Chun Ge
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Underlying Mechanism ◽  
Ros Generation ◽  
Down Regulation ◽  
Over Expression ◽  
And Function ◽  
Mcf 7

e12028 Background: Continuous exposure of breast cancer cells to adriamycin (ADR) induces the over-expression of P-glycoprotein (P-gp) and multiple drug resistance. However, the biochemical process and underlying mechanisms are not clear. Our previous study revealed that ADR increased reactive oxygen species (ROS) generation and reduced glutathione (GSH) biosynthesis, while N-acetylcysteine, the ROS scavenger, reversed the over-expressed P-gp induced by ADR. Methods: Based on MCF-7 breast cancer cells and the adriamycin-resistant MCF-7 subline (MCF-7R), we investigated the P-gp expression on mRNA, protein and function level by qPCR, western blotting, flow cytometry and laser scanning confocal and so on, under SLC7A11 down-regulation/over-expression, cystine depletion/supplement, increased ROS generation and combined factors. Results: The present study showed that ADR inhibited cystine influx (source material of GSH) and SLC7A11 transporter (in charge of cystine uptake) in MCF-7 cells. For the first time, we showed that a down-regulation/silence of SLC7A11, or cystine deprivation, or an enhanced exposure of ROS agents directly and significantly increased P-gp expression; yet, a combination of either an inhibited/silenced SLC7A11 or cystine deprivation and an increased ROS dramatically promoted the P-gp expression in MCF-7 cells. On the contrary, an over-expression of SLC7A11, or sufficiently supplementary cystine, or scavenger of ROS significantly depressed P-gp expression and activity. Moreover, the down-regulation of SLC7A11 and cystine deprivation induced an elevation of ROS and P-gp that could be reversed by N-acetylcysteine. It was suggested that ROS and SLC7A11/cystine were the two relevant factors responsible for the upregulated expression and function of P-gp. Conclusions: This study provided the direct evidences suggesting that ROS triggered over-expression of P-gp and demonstrated that the combination of either an inhibition of SLC7A11 or cystine influx and elevated ROS was the underlying mechanism contributing to P-gp over-expression induced by ADR. It was indicated that the SLC7A11 might be a potential target modulating ADR resistance.

scholarly journals Curcumin Regulates ERCC1 Expression and Enhances Oxaliplatin Sensitivity in Resistant Colorectal Cancer Cells through Its Effects on miR-409-3p

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Wei Han ◽  
Hongli Yin ◽  
Hao Ma ◽  
Yi Wang ◽  
Desong Kong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Resistance Mechanism ◽  
Cancer Cell Line ◽  
Colorectal Cancer Cell Line ◽  
Pcr Analysis ◽  
Colorectal Cancer Cells ◽  
Ercc1 Expression

Background. Oxaliplatin (L-OHP) resistance is a major obstacle to the effective treatment of colorectal cancer. The resistance mechanism(s) of colorectal tumors to L-OHP may be related to the regulation of ERCC1 by cancer-expressed miRNAs, but no in-depth studies on the miRNAs that affect drug resistance have been performed. Curcumin (Cur) can reverse the drug resistance of cancer cells, but its effects on ERCC1 expression and miRNA profiles in colorectal cancer have not been studied. Methods. To study the regulation effect of curcumin on ERCC1 expression and its effects on miRNAs, the L-OHP-resistant colorectal cancer cell line HCT116/L-OHP was established. MTT assays were used to evaluate cell proliferation. Flow cytometry was used to investigate apoptotic induction. Western blot and RT-PCR analysis were used to evaluate the expression of drug-associated ERCC1, Bcl-2, GST-π, MRP, P-gp, and survivin. Results. HCT116//L-OHP cell lines were successfully established. The combination of L-OHP and curcumin could reduce L-OHP resistance in vitro. In addition, combination therapy inhibited the expression of ERCC1, Bcl-2, GST-π, MRP, P-gp, and survivin at the mRNA and protein level. Curcumin was found to inhibit ERCC1 through its ability to modulate miR-409-3p. Conclusion. Curcumin can overcome L-OHP resistance in colorectal cancer cells through its effects on miR-409-3p mediated ERCC1 expression.

scholarly journals Long noncoding RNA RP11-70C1.3 confers chemoresistance of breast cancer cells through miR-6736-3p/NRP-1 axis

2021 ◽  
Author(s):  
Lansheng Zhang ◽  
Xia Zheng ◽  
Anqi Shen ◽  
Daojin Hua ◽  
Panrong Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Noncoding Rna ◽  
Breast Cancer Cells ◽  
Underlying Mechanism ◽  
Breast Cancer Patients ◽  
Potential Therapeutic Target ◽  
Cancer Chemoresistance

Chemoresistance remains a major obstacle for improving the clinical outcome of patients with breast cancer. Recently, long noncoding RNAs (lncRNAs) have been implicated in breast cancer chemoresistance. However, the function and underlying mechanism are still largely unknown. Using lncRNA microarray, we identified 122 upregulated and 475 downregulated lncRNAs that might be related to the breast cancer chemoresistance. Among them, RP11-70C1.3 was one of the most highly expressed lncRNAs. In breast cancer patients, high RP11-70C1.3 expression predicted poor prognosis. Knockdown of RP11-70C1.3 inhibited the multidrug resistance of breast cancer cells in vitro and in vivo. Further investigations revealed that RP11-70C1.3 functioned as a competing endogenous RNA (ceRNA) for miR-6736-3p to increase NRP-1 expression. Notably, the rescue experiments showed that both miR-6736-3p inhibitor and NRP-1 overexpression could partly reverse the suppressive influence of RP11-70C1.3 knockdown on breast cancer chemoresistance. In conclusion, our study indicated that lncRNA RP11-70C1.3 regulated NRP-1 expression by sponging miR-6736-3p to confer chemoresistance of breast cancer cells. RP11-70C1.3 might be a potential therapeutic target in enhancing the clinical efficacy of chemotherapy in breast cancer.

scholarly journals Hyaluronic Acid-Targeted Stimuli-Sensitive Nanomicelles Co-Encapsulating Paclitaxel and Ritonavir to Overcome Multi-Drug Resistance in Metastatic Breast Cancer and Triple-Negative Breast Cancer Cells

2021 ◽  
Vol 22 (3) ◽  
pp. 1257 ◽  
Author(s):  
Vrinda Gote ◽  
Amar Deep Sharma ◽  
Dhananjay Pal
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Disulfide Bonds ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Multi Drug Resistance ◽  
Stimuli Sensitive

Active targeting and overcoming multi-drug resistance (MDR) can be some of the important attributes of targeted therapy for metastatic breast cancer (MBC) and triple-negative breast cancer (TNBC) treatment. In this study, we constructed a hyaluronic acid (HA)-decorated mixed nanomicelles-encapsulating chemotherapeutic agent paclitaxel (PTX) and P-glycoprotein inhibitor ritonavir (RTV). HA was conjugated to poly (lactide) co-(glycolide) (PLGA) polymer by disulfide bonds (HA-ss-PLGA). HA is a natural ligand for CD44 receptors overexpressed in breast cancer cells. Disulfide bonds undergo rapid reduction in the presence of glutathione, present in breast cancer cells. The addition of RTV can inhibit the P-gp and CYP3A4-mediated metabolism of PTX, thus aiding in reversing MDR and sensitizing the cells toward PTX. An in vitro uptake and cytotoxicity study in MBC MCF-7 and TNBC MDA-MB-231 cell lines demonstrated the effective uptake of the nanomicelles and drug PTX compared to non-neoplastic breast epithelium MCF-12A cells. Interestingly, in vitro potency determination showed a reduction in mitochondrial membrane potential and reactive oxygen species in breast cancer cell lines, indicating effective apoptosis of cancer cells. Thus, stimuli-sensitive nanomicelles along with HA targeting and RTV addition can effectively serve as a chemotherapeutic drug delivery agent for MBC and TNBC.

scholarly journals Indirubin suppresses 4T1 murine breast cancer in vitro and in vivo by induction of ferroptosis and up-regulation of Ptgs2

2021 ◽  
Author(s):  
Xiuping Kuang ◽  
Yingnan Jiang ◽  
Jiwei Huang ◽  
Yongzhi Guo ◽  
weixi Li
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Underlying Mechanism ◽  
Mechanism Study ◽  
Commercial Kits ◽  
4T1 Breast Cancer ◽  
Gsk 3Β

Abstract Background Indirubin, isolated from Indigo Naturals, is reported to have the inhibitory activity of MCF-7 human breast cancer cells in vitro. However, studies on its anti-breast cancer activity in vivo and underlying mechanism are insufficient. We explored whether indirubin could trigger ferroptosis of breast cancer cells to exert anti-tumor activity. Methods Bioinformatical analysis was performed to detected the expression of prostaglandin-endoperoxide synthase 2 (Ptgs2) in breast cancer tissues Ptgs2-related prognosis for patients with breast cancer. Growth of 4T1 cells was assessed using wound healing assay and MTT assay. The levels of 4-HNE, GPX4, PTGS2 and GSK-3β proteins were detected by Western blot, and the mRNA of Ptgs2 was tested by qPCR. The GSH and MDA were determined by commercial kits. Molecular docking was employed to study interaction between indirubin and GSK-3β. An 4T1 murine breast cancer was adopted to evaluate the in vivo antitumor activity of indirubin. Results Indirubin promoted ferroptosis of 4T1 breast cancer cells with deplete of GSH, increased MDA and 4-HNE level, as well as decreased GPX4 expression. Indirubin suppressed the growth of 4T1 breast tumor in vivo. Mechanism study showed indirubin up regulated Ptgs2 expression by promoting phosphorylation (Ser 9) of GSK-3β. Conclusions Indirubin suppresses 4T1 murine breast cancer in vitro and in vivo by induction of ferroptosis and up-regulation of Ptgs2.

scholarly journals The FBXW2–MSX2–SOX2 axis regulates stem cell property and drug resistance of cancer cells

2019 ◽  
Vol 116 (41) ◽  
pp. 20528-20538 ◽  
Author(s):  
Yuan Yin ◽  
Chuan-Ming Xie ◽  
Hua Li ◽  
Mingjia Tan ◽  
Guoan Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
E3 Ligase ◽  
Stem Cell Property ◽  
Sox2 Expression ◽  
Cell Property

SOX2 is a key transcription factor that plays critical roles in maintaining stem cell property and conferring drug resistance. However, the underlying mechanisms by which SOX2 level is precisely regulated remain elusive. Here we report that MLN4924, also known as pevonedistat, a small-molecule inhibitor of neddylation currently in phase II clinical trials, down-regulates SOX2 expression via causing accumulation of MSX2, a known transcription repressor of SOX2 expression. Mechanistic characterization revealed that MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds to MSX2 and promotes MSX2 ubiquitylation and degradation. Likewise, FBXW2 overexpression shortens the protein half-life of MSX2, whereas FBXW2 knockdown extends it. We further identified hypoxia as a stress condition that induces VRK2 kinase to facilitate MSX2–FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. Biologically, expression of FBXW2 or SOX2 promotes tumor sphere formation, which is blocked by MSX2 expression. By down-regulating SOX2 through inactivation of FBXW2 E3 ligase, MLN4924 sensitizes breast cancer cells to tamoxifen in both in vitro and in vivo cancer cell models. Thus, a negative cascade of the FBXW2–MSX2–SOX2 axis was established, which regulates stem cell property and drug resistance. Finally, an inverse correlation of expression was found between FBXW2 and MSX2 in lung and breast cancer tissues. Collectively, our study revealed an anticancer mechanism of MLN4924. By inactivating FBXW2, MLN4924 caused MSX2 accumulation to repress SOX2 expression, leading to suppression of stem cell property and sensitization of breast cancer cells to tamoxifen.

scholarly journals SNHG3 promotes proliferation and invasion by regulating the miR-101/ZEB1 axis in breast cancer

RSC Advances ◽  
2018 ◽  
Vol 8 (27) ◽  
pp. 15229-15240 ◽  
Author(s):  
Liang Chang ◽  
Zhuang Hu ◽  
Zhenyu Zhou ◽  
Hui Zhang
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Underlying Mechanism ◽  
Functional Roles ◽  
Proliferation And Invasion

In the present study, we investigated the expression and functional roles of SNHG3 in breast cancer cells, as well as the underlying mechanism of SNHG3 involved in the progression of breast cancerin vitroandin vivo.

scholarly journals Deamidated TPI is an efficacious target for cell-selective therapy in triple-negative breast cancer

2021 ◽  
Author(s):  
Sergio Enríquez-Flores ◽  
Luis A Flores-López ◽  
Ignacio de la Mora-de la Mora ◽  
Itzhel García-Torres ◽  
Isabel Gracia-Mora ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Underlying Mechanism ◽  
Glycolytic Enzyme ◽  
Glycation End Products ◽  
Novel Target ◽  
Selective Therapy

Human TPI (HsTPI) is a central and essential glycolytic enzyme for energy supply and is overexpressed in cancer cells. Here, we investigated HsTPI as a potential target for inducing cell death in triple-hormone receptor-negative breast cancer, which is highly dependent on glycolysis, and therapies for its treatment are limited. We found endogenous accumulation of deamidated HsTPI in human breast cancer cells, which might be caused by the lower activity of the HsTPI-degrading caspase-1 in breast cancer cells. In silico and in vitro analyses of deamidated HsTPI demonstrated the efficacy of thiol-reactive drugs in blocking enzyme activity. The cancer cells were selectively programmed to undergo apoptosis with thiol-reactive drugs by inducing the production of methylglyoxal (MGO) and advanced glycation-end products (AGEs). In vivo in mice, the thiol-reactive drug effectively inhibited the growth of human tumors by targeting HsTPI as an underlying mechanism. Our findings demonstrate deamidated HsTPI as a novel target to develop therapeutic strategies for treating cancers and other pathologies in which this post-translationally modified protein accumulates.

scholarly journals Kinase shRNA screening reveals that TAOK3 enhances microtubule-targeted drug resistance of breast cancer cells via the NF-κB signaling pathway

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Tsung-Ching Lai ◽  
Chih-Yeu Fang ◽  
Yi-Hua Jan ◽  
Hsiao-Ling Hsieh ◽  
Yi-Fang Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Paclitaxel Resistance ◽  
Paclitaxel Treatment

Abstract Background Chemotherapy is currently one of the most effective treatments for advanced breast cancer. Anti-microtubule agents, including taxanes, eribulin and vinca-alkaloids are one of the primary major anti-breast cancer chemotherapies; however, chemoresistance remains a problem that is difficult to solve. We aimed to discover novel candidate protein targets to combat chemoresistance in breast cancer. Methods A lentiviral shRNA-based high-throughput screening platform was designed and developed to screen the global kinome to find new therapeutic targets in paclitaxel-resistant breast cancer cells. The phenotypes were confirmed with alternative expression in vitro and in vivo. Molecular mechanisms were investigated using global phosphoprotein arrays and expression microarrays. Global microarray analysis was performed to determine TAOK3 and genes that induced paclitaxel resistance. Results A serine/threonine kinase gene, TAOK3, was identified from 724 screened kinase genes. TAOK3 shRNA exhibited the most significant reduction in IC50 values in response to paclitaxel treatment. Ectopic downregulation of TAOK3 resulted in paclitaxel-resistant breast cancer cells sensitize to paclitaxel treatment in vitro and in vivo. The expression of TAOK3 also was correlated to sensitivity to two other anti-microtubule drugs, eribulin and vinorelbine. Our TAOK3-modulated microarray analysis indicated that NF-κB signaling played a major upstream regulation role. TAOK3 inhibitor, CP43, and shRNA of NF-κB both reduced the paclitaxel resistance in TAOK3 overexpressed cells. In clinical microarray databases, high TAOK3 expressed breast cancer patients had poorer prognoses after adjuvant chemotherapy. Conclusions Here we identified TAOK3 overexpression increased anti-microtubule drug resistance through upregulation of NF-κB signaling, which reduced cell death in breast cancer. Therefore, inhibition of the interaction between TAOK3 and NF-κB signaling may have therapeutic implications for breast cancer patients treated with anti-microtubule drugs.

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