scholarly journals Nitric Oxide-Releasing Drug Glyceryl Trinitrate Targets JAK2/STAT3 Signaling, Migration and Invasion of Triple-Negative Breast Cancer Cells

2021 ◽  
Vol 22 (16) ◽  
pp. 8449
Author(s):  
Sarra Bouaouiche ◽  
Silvia Ghione ◽  
Randa Sghaier ◽  
Olivier Burgy ◽  
Cindy Racoeur ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glyceryl Trinitrate ◽  
Signaling Pathway ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
The Impact

Triple-negative breast cancer (TNBC) is a highly aggressive disease with invasive and metastasizing properties associated with a poor prognosis. The STAT3 signaling pathway has shown a pivotal role in cancer cell migration, invasion, metastasis and drug resistance of TNBC cells. IL-6 is a main upstream activator of the JAK2/STAT3 pathway. In the present study we examined the impact of the NO-donor glyceryl trinitrate (GTN) on the activation of the JAK2/STAT3 signaling pathway and subsequent migration, invasion and metastasis ability of TNBC cells through in vitro and in vivo experiments. We used a subtoxic dose of carboplatin and/or recombinant IL-6 to activate the JAK2/STAT3 signaling pathway and its functional outcomes. We found an inhibitory effect of GTN on the activation of the JAK2/STAT3 signaling, migration and invasion of TNBC cells. We discovered that GTN inhibits the activation of JAK2, the upstream activator of STAT3, and mediates the S-nitrosylation of JAK2. Finally, the effect of GTN (Nitronal) on lung metastasis was investigated to assess its antitumor activity in vivo.

Bt354 as a new STAT3 signaling pathway inhibitor against triple negative breast cancer

2018 ◽  
Vol 26 (10) ◽  
pp. 920-930 ◽  
Author(s):  
Yue Chen ◽  
Ming Ji ◽  
Shen Zhang ◽  
Nina Xue ◽  
Heng Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

scholarly journals Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Pradip Shahi Thakuri ◽  
Megha Gupta ◽  
Sunil Singh ◽  
Ramila Joshi ◽  
Eric Glasgow ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Protein Kinases ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Tnbc Cell

Abstract Background Cell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs. Methods We used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis. Results Fisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells. Conclusions We established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.

scholarly journals LncRNA GHET1 Promotes Hypoxia-Induced Glycolysis, Proliferation, and Invasion in Triple-Negative Breast Cancer Through the Hippo/YAP Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Yu Wang ◽  
Shuwei Liu
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Nuclear Translocation ◽  
Lactate Production ◽  
Glucose Consumption ◽  
Breast Epithelial Cell ◽  
Epithelial Cell Line

ObjectiveThis study was to assess the specific impacts and mechanism of lncRNA GHET1 in the development of triple-negative breast cancer (TNBC).MethodsThe lncRNA GHET1 expression in TNBC tissues and adjacent healthy tissues was detected by qRT-PCR, and its expression was then measured at the cellular level, including TNBC cells and human normal breast epithelial cell line MCF10A. On the completion of transfection of negative shRNA or lncRNA GHET1 shRNA, the TNBC cells, HCC1937 and MDA-MB-468, were then cultured in a normoxia or hypoxia environment, respectively. 5-Ethynyl-2′-deoxyuridine (EdU) assay, colony formation assay, and transwell assay were applicable to the determination of cell proliferation, cell viability, and invasion in each group, respectively. Reagent kits were used for testing glucose consumption and lactate production levels. HCC1937 cells with knockdown or overexpression of lncRNA GHET1 were injected into the nude mice, followed by the examination of resulting tumor volume and weight. The distribution and expression of Hippo/YAP signaling pathway-related proteins were probed using western blotting.ResultsHighly expressed lncRNA GHET1 in TNBC tissues and cells and induction of lncRNA GHET1 by hypoxia were proved. Knockdown of lncRNA GHET1 significantly reduced proliferation, viability, and invasion of TNBC cells, and decreased glucose consumption and lactate production levels under the hypoxia condition. Furthermore, lncRNA GHET1 knockdown decreased HIF-1α expression in hypoxia and significantly inhibited tumor development in vivo. Knockdown of lncRNA GHET1 increased the phosphorylation levels of LATS1 and Yes-associated protein (YAP) to retain YAP within the cytoplasm, while the overexpression of lncRNA GHET1 or hypoxia promoted nuclear translocation of YAP and TNBC development.ConclusionLncRNA GHET1 expression can be induced by hypoxia, which leads to excessive activation of the Hippo/YAP signaling pathway, thus promoting TNBC progression.

CircRNA circ-ERBB2 elevates Warburg effect and facilitates triple-negative breast cancer growth by the miR-136-5p/PDK4 axis

2021 ◽  
Author(s):  
Yihong Huang ◽  
Shuo Zheng ◽  
Ying Lin ◽  
Liming Ke
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Warburg Effect ◽  
Triple Negative ◽  
Pyruvate Dehydrogenase Kinase ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Loss Of Function

Triple negative breast cancer (TNBC) is an aggressive histological subtype of breast cancer. It has been reported that that circRNA circ-ERBB2 (circBase ID: hsa_circ_0007766) is mainly distributed in the cytoplasm of TNBC cells and promotes the proliferation and invasion of TNBC cells. This study aimed to explore the molecular mechanism of circ-ERBB2 regulating the progression of TNBC. Expression of circ-ERBB2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Loss-of-function experiments were performed to investigate the function of circ-ERBB2 in TNBC cells in vitro and in vivo . The regulatory mechanism of circ-ERBB2 was surveyed by bioinformatics analysis, dual-luciferase reporter and RNA immunoprecipitation (RIP) or RNA pull-down assays. We observed that Circ-ERBB2 was overexpressed in TNBC, and TNBC patients with high circ-ERBB2 expression had a poor prognosis. Functionally, circ-ERBB2 knockdown constrained TNBC growth in vivo and reduced Warburg effect, accelerated apoptosis, repressed proliferation, migration, and invasion of TNBC cell in vitro . Mechanically, circ-ERBB2 sponged miR-136-5p to elevate pyruvate dehydrogenase kinase 4 (PDK4) expression. In conclusion, circ-ERBB2 facilitated Warburg effect and malignancy of TNBC cells by the miR-136-5p/PDK4 pathway, at least in part. This study supported circ-ERBB2 as a prognostic indicator for TNBC.

scholarly journals Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Binlong Zhong ◽  
Deyao Shi ◽  
Fashuai Wu ◽  
Shangyu Wang ◽  
Hongzhi Hu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Mapk Pathway ◽  
Migration And Invasion ◽  
G1 Arrest ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Candidate Drug

Abstract Osteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients’ health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.

scholarly journals SphK2/S1P promotes metastasis in triple negative breast cancer through PAK1/LIMK1/Cofilin1 signaling pathway

2020 ◽  
Author(s):  
Weiwei Shi ◽  
Ding Ma ◽  
Yin Cao ◽  
Lili Hu ◽  
Shuwen Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Signaling Pathway ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Specific Inhibitor ◽  
Downstream Signaling

Abstract Background: Triple negative breast cancer (TNBC) features poor prognosis which partialy attributed to the high metastasis rate. However, there is no effective target for systemic TNBC therapy due to the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors (ER, PR, HER-2) up to date. In the present study, we evaluated the role of sphingosine kinase 2 (SphK2) and its catalysate sphingosine-1-phosphate (S1P) in TNBC metastasis, and the antitumor activity of SphK2 specific inhibitor ABC294640 in TNBC metastasis. Methods: The function of SphK2 and S1P in migration of TNBC cells was evaluated by Transwell migration and wound healing assays. The molecular mechanisms of SphK2/S1P mediating TNBC metastasis were investigated using cell line establishment, western blot, histological examination and immunohistochemistry assays. The antitumor activity of ABC294640 was examined in TNBC lung metastasis model in vivo. Results: SphK2 regulated TNBC cells migration through the generation of S1P. Targeting SphK2 with ABC294640 inhibited TNBC lung metastasis in vivo . p21-activated kinase 1 (PAK1), p-Lin-11/Isl-1/Mec-3 kinase 1 (LIMK1) and Cofilin1 was the downstream signaling cascade of SphK2/S1P. Inhibition of PAK1 suppressed SphK2/S1P induced TNBC cells migration. Concusion: SphK2/S1P promotes TNBC metastasis through the activation of the PAK1/LIMK1/Cofilin1 signaling pathway. ABC294640 potently inhibits TNBC metastasis in vivo which could be developed as a novel agent for the clinical treatment of TNBC.

scholarly journals Hyperinsulinemia promotes aberrant histone acetylation in triple negative breast cancer

2018 ◽  
Author(s):  
Parijat Senapati ◽  
Christine Thai ◽  
Angelica Sanchez ◽  
Emily J Gallagher ◽  
Derek LeRoith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Histone Acetylation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Prognostic Indicator ◽  
Gene Promoters ◽  
Genome Wide ◽  
Altered Gene ◽  
The Impact

AbstractExcess levels of insulin relative to glucose in the blood, or hyperinsulinemia, is considered to be a poor prognostic indicator for patients with triple negative breast cancer (TNBC). While this association has been recognized for some time, the mechanistic role of hyperinsulinemia in promoting TNBC remains unclear. We show that insulin treatment leads to genome-wide increase in histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway in MDA-MB-231 cells. Genome-wide analysis showed that the increase in histone acetylation occurs primarily at gene promoters. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. In vivo, hyperinsulinemia also enhances growth of MDA-MB-231 derived tumors through increased histone acetylation. These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.

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