PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial–Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In Vitro

Metastasis accounts for the vast majority of deaths in breast cancer, and novel and effective treatments to inhibit cancer metastasis remain urgently developed. The expression level of heat shock protein 90 (HSP90) in invasive breast cancer tissue is higher than in adjacent non-cancerous tissue. In the present study, we investigated the inhibitory effect of penisuloxazin A (PNSA), a novel C- terminal inhibitor of HSP90, on metastasis of breast cancer cells and related mechanism in vitro. We found that PNSA obviously affected adhesion, migration, and invasion of triple-negative breast cancer (TNBC) MDA-MB-231 cells and Trastuzumab-resistant JIMT-1 cells. Furthermore, PNSA was capable of reversing epithelial–mesenchymal transformation (EMT) of MDA-MB-231 cells with change of cell morphology. PNSA increases E-cadherin expression followed by decreasing amounts of N-cadherin, vimentin, and matrix metalloproteinases9 (MMP9) and proteolytic activity of matrix metalloproteinases2 (MMP2) and MMP9. Comparatively, the N-terminal inhibitor of HSP90 17-allyl-17-demethoxygeldanamycin (17-AAG) had no effect on EMT of MDA-MB-231 cells. PNSA was uncovered to reduce the stability of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) proteins and thereby inhibiting their downstream signaling transductions by inhibition of HSP90. In addition, PNSA reduced the expression of programmed cell death-ligand 1 (PD-L1) to promote natural killer (NK) cells to kill breast cancer cells with a dose far less than that of cytotoxicity to NK cell itself, implying the potential of PNSA to enhance immune surveillance against metastasis in vivo. All these results indicate that PNSA is a promising anti-metastasis agent worthy of being studied in the future.

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Alcohol Stimulates Activation of Snail, Epidermal Growth Factor Receptor Signaling, and Biomarkers of EpithelialâMesenchymal Transition in Colon and Breast Cancer Cells

Alcoholism Clinical and Experimental Research ◽

10.1111/j.1530-0277.2009.01061.x ◽

2010 ◽

Vol 34 (1) ◽

pp. 19-31 ◽

Cited By ~ 52

Author(s):

Christopher B. Forsyth ◽

Yueming Tang ◽

Maliha Shaikh ◽

Lijuan Zhang ◽

Ali Keshavarzian

Keyword(s):

Breast Cancer ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Growth Factor Receptor ◽

Mesenchymal Transition ◽

Epidermal Growth ◽

Growth Factor Receptor Signaling

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Vascular Endothelial Growth Factor Receptor-1 Activation Promotes Migration and Invasion of Breast Cancer Cells through Epithelial-Mesenchymal Transition

PLoS ONE ◽

10.1371/journal.pone.0065217 ◽

2013 ◽

Vol 8 (6) ◽

pp. e65217 ◽

Cited By ~ 29

Author(s):

Qian Ning ◽

Caigang Liu ◽

Lei Hou ◽

Min Meng ◽

Xiaojin Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Growth Factor Receptor ◽

Migration And Invasion ◽

Vascular Endothelial ◽

Mesenchymal Transition ◽

Endothelial Growth Factor

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NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth

Cancers ◽

10.3390/cancers13112682 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2682

Author(s):

Keshav Karki ◽

Kumaravel Mohankumar ◽

Abigail Schoeller ◽

Gregory Martin ◽

Rupesh Shrestha ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Cell Growth ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cells ◽

Growth Factor Receptor ◽

Migration And Invasion ◽

Binding Studies

Nuclear receptor 4A1 (NR4A1, Nur77, TR3) is more highly expressed in breast and solid tumors compared to non-tumor tissues and is a pro-oncogenic factor in solid tumor-derived cancers. NR4A1 regulates cancer cell growth, survival, migration, and invasion, and bis-indole-derived compounds (CDIMs) that bind NR4A1 act as antagonists and inhibit tumor growth. Preliminary structure-binding studies identified 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl)methane analogs as NR4A1 ligands with low KD values; we further investigated the anticancer activity of the four most active analogs (KD’s ≤ 3.1 µM) in breast cancer cells and in athymic mouse xenograft models. The treatment of MDA-MB-231 and SKBR3 breast cancer cells with the 3-bromo-5-methoxy, 3-chloro-5-trifluoromethoxy, 3-chloro-5-trifluoromethyl, and 3-bromo-5-trifluoromethoxy phenyl-substituted analogs decreased cell growth and the expression of epidermal of growth factor receptor (EGFR), hepatocyte growth factor receptor (cMET), and PD-L1 as well as inhibited mTOR phosphorylation. In addition, all four compounds inhibited tumor growth in athymic nude mice bearing MDA-MB-231 cells (orthotopic) at a dose of 1 mg/kg/d, which was not accompanied by changes in body weight. These 3,5-disubstituted analogs were the most potent CDIM/NR4A1 ligands reported and are being further developed for clinical applications.

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FBXL10 promotes EMT and metastasis of breast cancer cells via regulating the acetylation and transcriptional activity of SNAI1

Cell Death Discovery ◽

10.1038/s41420-021-00722-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yangyang Yang ◽

Binggong Zhao ◽

Linlin Lv ◽

Yuxi Yang ◽

Shujing Li ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Bioinformatics Analyses ◽

Positive Role ◽

Mesenchymal Transition ◽

E Cadherin

AbstractF-box and leucine-rich repeat protein 10 (FBXL10) has been reported to play a regulatory role in the initiation and development of breast cancer. Bioinformatics analyses revealed that FBXL10 may involve in the process of cytoskeleton organization. This research aimed to investigate the function of FBXL10 in epithelial-mesenchymal transition (EMT) and metastasis of breast cancer, and tried to reveal the molecular mechanism involved in this issue. Functional experiments in vitro revealed that FBXL10 promoted the migration and invasion of breast cancer cells through inhibiting E-cadherin expression and inducing EMT. Mechanical studies revealed that FBXL10 could specifically interact with SNAI1, but not Slug or ZEB1. And it promoted the transcriptional repression activity of SNAI1 on CDH1 in breast cancer cells. Furthermore, FBXL10 had a positive role for the deacetylation of SNAI1 by facilitating the interaction between SNAI1 and HDAC1, a dominating deacetylase of SNAI1. And the deacetylated SNAI1 showed a more suppressive ability to inhibit the transcription of E-cadherin. Moreover, mouse models were also conducted to confirm the effect of FBXL10 on the lung metastasis of breast cancer in vivo. Totally, our data revealed that FBXL10 served as a pro-metastatic factor in breast cancer via repressing the expression of E-cadherin and inducing EMT. It may provide a novel regulatory axis in the EMT of breast cancer.

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Enhancement of Breast Cancer Cell Aggressiveness by lncRNA H19 and its Mir-675 Derivative: Insight into Shared and Different Actions

Cancers ◽

10.3390/cancers12071730 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1730

Author(s):

Evodie Peperstraete ◽

Clément Lecerf ◽

Jordan Collette ◽

Constance Vennin ◽

Ludivine Raby ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Public Health Problem ◽

Migration And Invasion ◽

Transgenic Zebrafish ◽

Major Public Health Problem ◽

Mesenchymal Transition

Breast cancer is a major public health problem and the leading world cause of women death by cancer. Both the recurrence and mortality of breast cancer are mainly caused by the formation of metastasis. The long non-coding RNA H19, the precursor of miR-675, is involved in breast cancer development. The aim of this work was to determine the implication but, also, the relative contribution of H19 and miR-675 to the enhancement of breast cancer metastatic potential. We showed that both H19 and miR-675 increase the invasive capacities of breast cancer cells in xenografted transgenic zebrafish models. In vitro, H19 and miR-675 enhance the cell migration and invasion, as well as colony formation. H19 seems to induce the epithelial-to-mesenchymal transition (EMT), with a decreased expression of epithelial markers and an increased expression of mesenchymal markers. Interestingly, miR-675 simultaneously increases the expression of both epithelial and mesenchymal markers, suggesting the induction of a hybrid phenotype or mesenchymal-to-epithelial transition (MET). Finally, we demonstrated for the first time that miR-675, like its precursor H19, increases the stemness properties of breast cancer cells. Altogether, our data suggest that H19 and miR-675 could enhance the aggressiveness of breast cancer cells through both common and different mechanisms.

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