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 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.

Intermedin promotes breast cancer metastasis via Src/c-Myc-mediated ribosome production and protein translation

2021 ◽  
Author(s):  
Lingmiao Kong ◽  
Fei Xiao ◽  
Yong'gang Wei ◽  
Zhongxue Feng ◽  
Min Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Ribosome Biogenesis ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Protein Translation ◽  
Underlying Mechanism ◽  
Breast Cancer Metastasis ◽  
Novel Target

Abstract Background Breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-associated mortality in women worldwide. Intermedin (IMD) is an endogenous peptide that belongs to the calcitonin gene-related peptide family and has been reported to play important roles in several types of cancers, including breast cancer. In this study, we sought to investigate how IMD affects the behavior of breast cancer cells, the underlying mechanism of these effects, and whether blockade of IMD has a therapeutic effect against breast cancer. Methods Transcriptome sequencing (RNA-Seq), cell biological experiments, Western blotting (WB), immunoprecipitation (IP), and animal tumor models were used. Results IMD expression was significantly increased in breast cancer samples, and the IMD level was positively correlated with lymph node metastasis and Ki67 expression. Cell biological experiments showed that IMD promoted the anchorage-independent growth, migration, and invasive ability of breast cancer cells. Inhibiting IMD activity with an anti-IMD monoclonal antibody blocked these tumor-promoting effects. In addition, blockade of IMD reduced in situ tumor growth and significantly decreased lung metastasis of 4T1 breast cancer in vivo. IMD induced Src kinase phosphorylation, which triggered the transcription of c-Myc, a major oncoprotein controlling the expression of genes that encode ribosomal components. Our data suggest that IMD is involved in breast cancer cell invasion and metastasis, potentially through increasing ribosome biogenesis and protein translation via the Src/c-Myc signaling pathway. Conclusion These results suggest that IMD may be a novel target for the treatment of breast cancer.

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 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.

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

scholarly journals Controllable Drug Delivery by Na+/K+ ATPase α1 Targeting Peptide Conjugated DSPE-PEG Nanocarriers for Breast Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382110278
Author(s):  
Yayan Yang ◽  
Qian Feng ◽  
Chuanfeng Ding ◽  
Wei Kang ◽  
Xiufeng Xiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Click Reaction ◽  
Chemotherapy Drugs ◽  
Targeting Peptide ◽  
And Migration

Although Epirubicin (EPI) is a commonly used anthracycline for the treatment of breast cancer in clinic, the serious side effects limit its long-term administration including myelosuppression and cardiomyopathy. Nanomedicines have been widely utilized as drug delivery vehicles to achieve precise targeting of breast cancer cells. Herein, we prepared a DSPE-PEG nanocarrier conjugated a peptide, which targeted the breast cancer overexpression protein Na+/K+ ATPase α1 (NKA-α1). The nanocarrier encapsulated the EPI and grafted with the NKA-α1 targeting peptide through the click reaction between maleimide and thiol groups. The EPI was slowly released from the nanocarrier after entering the breast cancer cells with the guidance of the targeting NKA-α1 peptide. The precise and controllable delivery and release of the EPI into the breast cancer cells dramatically inhibited the cells proliferation and migration in vitro and suppressed the tumor volume in vivo. These results demonstrate significant prospects for this nanocarrier as a promising platform for numerous chemotherapy drugs.

scholarly journals Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 480
Author(s):  
Rakshitha Pandulal Miskin ◽  
Janine S. A. Warren ◽  
Abibatou Ndoye ◽  
Lei Wu ◽  
John M. Lamar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Cell Invasion ◽  
Breast Cancer Cells ◽  
Gene Promoter ◽  
Akt Inhibitor ◽  
Integrin Α3β1

In the current study, we demonstrate that integrin α3β1 promotes invasive and metastatic traits of triple-negative breast cancer (TNBC) cells through induction of the transcription factor, Brain-2 (Brn-2). We show that RNAi-mediated suppression of α3β1 in MDA-MB-231 cells caused reduced expression of Brn-2 mRNA and protein and reduced activity of the BRN2 gene promoter. In addition, RNAi-targeting of Brn-2 in MDA-MB-231 cells decreased invasion in vitro and lung colonization in vivo, and exogenous Brn-2 expression partially restored invasion to cells in which α3β1 was suppressed. α3β1 promoted phosphorylation of Akt in MDA-MB-231 cells, and treatment of these cells with a pharmacological Akt inhibitor (MK-2206) reduced both Brn-2 expression and cell invasion, indicating that α3β1-Akt signaling contributes to Brn-2 induction. Analysis of RNAseq data from patients with invasive breast carcinoma revealed that high BRN2 expression correlates with poor survival. Moreover, high BRN2 expression positively correlates with high ITGA3 expression in basal-like breast cancer, which is consistent with our experimental findings that α3β1 induces Brn-2 in TNBC cells. Together, our study demonstrates a pro-invasive/pro-metastatic role for Brn-2 in breast cancer cells and identifies a role for integrin α3β1 in regulating Brn-2 expression, thereby revealing a novel mechanism of integrin-dependent breast cancer cell invasion.

In vitro evaluation of estrogenic, antiestrogenic and antitumor effects of amentoflavone

2021 ◽  
pp. 096032712199945
Author(s):  
AT Aliyev ◽  
S Ozcan-Sezer ◽  
A Akdemir ◽  
H Gurer-Orhan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Antitumor Effects ◽  
Antiestrogenic Activity ◽  
Er Positive ◽  
In Vivo Effects ◽  
Mcf 7

Apigenin, a flavonoid, is reported to act as an estrogen receptor (ER) agonist and inhibit aromatase enzyme. However, amentoflavone, a biflavonoid bearing two apigenin molecules, has not been evaluated for its endocrine modulatory effects. Besides, it is highly consumed by young people to build muscles, enhance mood and lose weight. In the present study, apigenin was used as a reference molecule and ER mediated as well as ER-independent estrogenic/antiestrogenic activity of amentoflavone was investigated. Antitumor activity of amentoflavone was also investigated in both ER positive (MCF-7 BUS) and triple-negative (MDA-MB-231) breast cancer cells and its cytotoxicity was evaluated in human breast epithelial cells (MCF-10A). Our data confirmed ER agonist, aromatase inhibitory and cytotoxic effects of apigenin in breast cancer cells, where no ER mediated estrogenic effect and physiologically irrelevant, slight, aromatase inhibition was found for amentoflavone. Although selective cytotoxicity of amentoflavone was found in MCF-7 BUS cells, it does not seem to be an alternative to the present cytotoxic drugs. Therefore, neither an adverse effect, mediated by an estrogenic/antiestrogenic effect of amentoflavone nor a therapeutical benefit would be expected from amentoflavone. Further studies could be performed to investigate its in vivo effects.

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