scholarly journals Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2795
Author(s):  
Aadhya Tiwari ◽  
Mari Iida ◽  
Corinna Kosnopfel ◽  
Mahyar Abbariki ◽  
Apostolos Menegakis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Triple Negative ◽  
Mapk Pathway ◽  
Binding Protein ◽  
Akt Pathway ◽  
Breast Cancers ◽  
Gain Of Function ◽  
Multifunctional Protein ◽  
Cancer Hallmarks ◽  
The Individual

The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in KRAS mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (PIK3CA). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in KRAS(G13D)-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus PIK3CA(H1047R)/PTEN(E307K) mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in KRAS-mutated cells is mainly dependent on the MAPK/ERK pathway, while in PIK3CA/PTEN-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.

Abstract 3658: A novel microtubule associated RNA binding protein matrin 3 act as a tumor suppressor by regulating mitotic spindle organizing proteins in triple negative breast cancers

2016 ◽  
Author(s):  
Panneerdoss Subbarayalu ◽  
Subapriya Rajamanickam ◽  
Suryavathi Viswanadhapalli ◽  
Benjamin C. Onyeagucha ◽  
Vijay K. Eedunuri ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Mitotic Spindle ◽  
Triple Negative ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Breast Cancers ◽  
Matrin 3

scholarly journals Targeting Insulin-Like Growth Factor Binding Protein-3 Signaling in Triple-Negative Breast Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Kamila A. Marzec ◽  
Robert C. Baxter ◽  
Janet L. Martin
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Breast Cancers ◽  
Novel Therapy ◽  
Factor Binding ◽  
Igfbp 3

Insulin-like growth factor binding protein-3 (IGFBP-3) is a key regulatory molecule of the IGF axis and can function in a tissue-specific way as both a tumor suppressor and promoter. Triple-negative breast cancer (TNBC) has high tumor expression of IGFBP-3 associated with markers of poor prognosis and, although accounting for 15–20% of all breast cancers, is responsible for disproportionate rates of morbidity and mortality. Because they lack estrogen and progesterone receptors and overexpression of HER2, TNBC are resistant to treatments that target these molecules, making the development of new therapies an important goal. In addition to frequent high expression of IGFBP-3, these tumors also express EGFR highly, but targeting EGFR signaling alone in TNBC has been of little success. Identification of a functional growth-stimulatory interaction between EGFR and IGFBP-3 signaling prompted investigation into cotargeting these pathways as a novel therapy for TNBC. This involves inhibition of both EGFR kinase activity and a mediator of IGFBP-3’s stimulatory bioactivity, sphingosine kinase-1 (SphK1), and has shown promise in a preclinical setting. Functional interaction between EGFR and IGFBP-3 may also promote chemoresistance in TNBC, and delineating the mechanisms involved may identify additional targets for development of therapies in cancers that express both IGFBP-3 and EGFR.

scholarly journals Phosphorylation of MNAR Promotes Estrogen Activation of Phosphatidylinositol 3-Kinase

2006 ◽  
Vol 27 (5) ◽  
pp. 1904-1913 ◽  
Author(s):  
James G. Greger ◽  
Natalie Fursov ◽  
Neil Cooch ◽  
Sean McLarney ◽  
Leonard P. Freedman ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Regulatory Subunit ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Mcf7 Cells ◽  
Control Of Gene Expression ◽  
Novel Scaffold ◽  
Phosphatidylinositol 3

ABSTRACT Estrogen actions are mediated by a complex interface of direct control of gene expression (the so-called “genomic action”) and by regulation of cell signaling/phosphorylation cascades, referred to as the “nongenomic,” or extranuclear, action. We have previously described the identification of MNAR (modulator of nongenomic action of estrogen receptor) as a novel scaffold protein that regulates estrogen receptor alpha (ERα) activation of cSrc. In this study, we have investigated the role of MNAR in 17β-estradiol (E2)-induced activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Consistent with our previous results, a direct correlation was established between MNAR expression levels and E2-induced activation of PI3 and Akt kinases. Endogenous MNAR, ERα, cSrc, and p85, the regulatory subunit of PI3 kinase, interacted in MCF7 cells treated with E2. The interaction between p85 and MNAR required activation of cSrc and MNAR phosphorylation on Tyr 920. Consequently, the mutation of this tyrosine to alanine (Y920A) abrogated the interaction between MNAR and p85 and the E2-induced activation of the PI3K/Akt pathway, which was required for the E2-induced protection of MCF7 cells from apoptosis. Nonetheless, the Y920A mutant potentiated the E2-induced activation of the Src/MAPK pathway and MCF7 cell proliferation, as observed with the wild-type MNAR. These results provide new and important insights into the molecular mechanisms of E2-induced regulation of cell proliferation and apoptosis.

scholarly journals Targeting p90 Ribosomal S6 Kinase Eliminates Tumor-Initiating Cells by Inactivating Y-Box Binding Protein-1 in Triple-Negative Breast Cancers

Stem Cells ◽  
2012 ◽  
Vol 30 (7) ◽  
pp. 1338-1348 ◽  
Author(s):  
Anna L. Stratford ◽  
Kristen Reipas ◽  
Kaiji Hu ◽  
Abbas Fotovati ◽  
Rachel Brough ◽  
...  
Keyword(s):  
Triple Negative ◽  
Binding Protein ◽  
Breast Cancers ◽  
Tumor Initiating Cells ◽  
S6 Kinase ◽  
P90 Ribosomal S6 Kinase ◽  
Ribosomal S6 Kinase

scholarly journals M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Fang Dong ◽  
Shengnan Ruan ◽  
Jinlong Wang ◽  
Yun Xia ◽  
Kehao Le ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Triple Negative Breast Cancer ◽  
Noncoding Rna ◽  
Triple Negative ◽  
M2 Macrophage ◽  
Breast Cancers ◽  
The Impact

Abstract As a common female malignancy, triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancers (BC). This study further studied the role of long noncoding RNA (lncRNA) prostate cancer-associated transcript 6 (PCAT6) in TNBC. Functional assays, including EdU, wound healing, transwell, and immunofluorescence staining, revealed the effect of PCAT6 on cell proliferation, migration, and EMT process. The tube-formation assay disclosed the function of PCAT6 on angiogenesis. In vivo assays were also established to explore the impact of PCAT6 on tumor growth and microangiogenesis. The results revealed that PCAT6 boosted TNBC cell proliferation, migration, and angiogenesis both in vitro and in vivo. Then, this study unveiled that M2 macrophage secreted VEGF to stimulate the upregulation of PCAT6, thus promoting angiogenesis in TNBC. Next, through bioinformatics analysis and mechanism assays, we identified that PCAT6 positively regulated VEGFR2 expression via ceRNA pattern and then participated in VEGFR/AKT/mTOR signaling pathway to accelerate angiogenesis. Moreover, PCAT6 bound USP14, a deubiquitinase, to induce the deubiquitination of VEGFR2. On the whole, M2 macrophage-induced upregulation of PCAT6 facilitates TNBC tumorigenesis through modulation of VEGFR2 expression via ceRNA and deubiquitination patterns.

scholarly journals SARAF and EFHB Modulate Store-Operated Ca2+ Entry and Are Required for Cell Proliferation, Migration and Viability in Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4160
Author(s):  
Isaac Jardin ◽  
Joel Nieto-Felipe ◽  
Sandra Alvarado ◽  
Raquel Diez-Bello ◽  
Jose J. Lopez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Point Of View ◽  
Mcf7 Cells ◽  
Cancer Hallmarks ◽  
Essential Components

Breast cancer is among the most common malignancies in women. From the molecular point of view, breast cancer can be grouped into different categories, including the luminal (estrogen receptor positive (ER+)) and triple negative subtypes, which show distinctive features and, thus, are sensitive to different therapies. Breast cancer cells are strongly dependent on Ca2+ influx. Store-operated Ca2+ entry (SOCE) has been found to support a variety of cancer hallmarks including cell viability, proliferation, migration, and metastasis. The Ca2+ channels of the Orai family and the endoplasmic reticulum Ca2+ sensor STIM1 are the essential components of SOCE, but the extent of Ca2+ influx is fine-tuned by several regulatory proteins, such as the STIM1 modulators SARAF and EFHB. Here, we show that the expression and/or function of SARAF and EFHB is altered in breast cancer cells and both proteins are required for cell proliferation, migration, and viability. EFHB expression is upregulated in luminal and triple negative breast cancer (TNBC) cells and is essential for full SOCE in these cells. SARAF expression was found to be similar in breast cancer and pre-neoplastic breast epithelial cells, and SARAF knockdown was found to result in enhanced SOCE in pre-neoplastic and TNBC cells. Interestingly, silencing SARAF expression in ER+ MCF7 cells led to attenuation of SOCE, thus suggesting a distinctive role for SARAF in this cell type. Finally, we used a combination of approaches to show that molecular knockdown of SARAF and EFHB significantly attenuates the ability of breast cancer cells to proliferate and migrate, as well as cell viability. In aggregate, SARAF and EFHB are required for the fine modulation of SOCE in breast cancer cells and play an important role in the maintenance of proliferation, migration, and viability in these cells.

scholarly journals Sericin inhibits MDA‑MB‑468 cell proliferation via the PI3K/Akt pathway in triple‑negative breast cancer

2020 ◽  
Vol 23 (2) ◽  
Author(s):  
Lin Niu ◽  
Songhe Yang ◽  
Xueying Zhao ◽  
Xiaochao Liu ◽  
Lina Si ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Akt Pathway

scholarly journals Thiol-independent interaction of protein disulphide isomerase with type X collagen during intra-cellular folding and assembly

1998 ◽  
Vol 331 (3) ◽  
pp. 793-800 ◽  
Author(s):  
Stephen H. McLAUGHLIN ◽  
Neil J. BULLEID
Keyword(s):  
Molecular Chaperone ◽  
Binding Protein ◽  
Type X Collagen ◽  
Protein Disulphide Isomerase ◽  
Multifunctional Protein ◽  
Permeabilized Cells ◽  
Helix Formation ◽  
Cellular Context ◽  
The Individual

Protein disulphide isomerase (PDI) has been shown to be a multifunctional protein capable of catalysing disulphide-bond formation and isomerization, and of participating as a non-catalytic subunit of prolyl 4-hydroxylase (P4-H) and microsomal triacylglycerol transfer protein. It has also been proposed to function as a molecular chaperone during the refolding of denatured proteins in vitro. To investigate its potential role as a molecular chaperone within a cellular context, we studied the folding, modification and assembly of type X collagen in semi-permeabilized cells. Using this approach, we demonstrate that depletion of ATP has no effect on the rate or extent of helix formation, indicating that the individual triple helical regions do not interact with the molecular chaperone immunoglobulin heavy-chain binding protein (BiP). However, PDI was shown to interact transiently with type X during helix formation in a role related to its function as the β subunit of P4-H. Once the collagen triple helix was formed, PDI re-associated, indicating a role in preventing the premature assembly of this molecule into higher-order structures. This interaction was not thiol dependent, as a type X polypeptide that did not contain any cysteine residues was able to fold correctly and interact with PDI. Both PDI and the collagen-binding protein hsp47 showed a similar pH-dependent interaction with folded collagen, dissociating when the pH was lowered to pH 6.0. These results suggest a role for PDI in chaperoning type X collagen during its transport through the cell.

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