scholarly journals Polyphenols Modulating Effects of PD-L1/PD-1 Checkpoint and EMT-Mediated PD-L1 Overexpression in Breast Cancer

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1718
Author(s):  
Samia S. Messeha ◽  
Najla O. Zarmouh ◽  
Karam F. A. Soliman
Keyword(s):  
Breast Cancer ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Antitumor Agents ◽  
Transforming Growth Factor ◽  
Close Association ◽  
Immune Surveillance ◽  
Cell Phenotype ◽  
Mesenchymal Transition

Investigating dietary polyphenolic compounds as antitumor agents are rising due to the growing evidence of the close association between immunity and cancer. Cancer cells elude immune surveillance for enhancing their progression and metastasis utilizing various mechanisms. These mechanisms include the upregulation of programmed death-ligand 1 (PD-L1) expression and Epithelial-to-Mesenchymal Transition (EMT) cell phenotype activation. In addition to its role in stimulating normal embryonic development, EMT has been identified as a critical driver in various aspects of cancer pathology, including carcinogenesis, metastasis, and drug resistance. Furthermore, EMT conversion to another phenotype, Mesenchymal-to-Epithelial Transition (MET), is crucial in developing cancer metastasis. A central mechanism in the upregulation of PD-L1 expression in various cancer types is EMT signaling activation. In breast cancer (BC) cells, the upregulated level of PD-L1 has become a critical target in cancer therapy. Various signal transduction pathways are involved in EMT-mediated PD-L1 checkpoint overexpression. Three main groups are considered potential targets in EMT development; the effectors (E-cadherin and Vimentin), the regulators (Zeb, Twist, and Snail), and the inducers that include members of the transforming growth factor-beta (TGF-β). Meanwhile, the correlation between consuming flavonoid-rich food and the lower risk of cancers has been demonstrated. In BC, polyphenols were found to downregulate PD-L1 expression. This review highlights the effects of polyphenols on the EMT process by inhibiting mesenchymal proteins and upregulating the epithelial phenotype. This multifunctional mechanism could hold promises in the prevention and treating breast cancer.

scholarly journals Loss of BRMS1 Promotes a Mesenchymal Phenotype through NF-κB-Dependent Regulation ofTwist1

2014 ◽  
Vol 35 (1) ◽  
pp. 303-317 ◽  
Author(s):  
Yuan Liu ◽  
Marty W. Mayo ◽  
Aizhen Xiao ◽  
Emily H. Hall ◽  
Elianna B. Amin ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Breast Cancer Metastasis ◽  
Metastasis Suppressor ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Metastasis Suppressor 1 ◽  
Promoter Occupancy

Breast cancer metastasis suppressor 1 (BRMS1) is downregulated in non-small cell lung cancer (NSCLC), and its reduction correlates with disease progression. Herein, we investigate the mechanisms through which loss of theBRMS1gene contributes to epithelial-to-mesenchymal transition (EMT). Using a short hairpin RNA (shRNA) system, we show that loss of BRMS1 promotes basal and transforming growth factor beta-induced EMT in NSCLC cells. NSCLC cells expressingBRMS1shRNAs (BRMS1knockdown [BRMS1KD]) display mesenchymal characteristics, including enhanced cell migration and differential regulation of the EMT markers. Mesenchymal phenotypes observed inBRMS1KDcells are dependent on RelA/p65, the transcriptionally active subunit of nuclear factor kappa B (NF-κB). In addition, chromatin immunoprecipitation analysis demonstrates that loss ofBRMS1increasesTwist1promoter occupancy of RelA/p65 K310—a key histone modification associated with increased transcription. Knockdown ofTwist1results in reversal ofBRMS1KD-mediated EMT phenotypic changes. Moreover, in our animal model,BRMS1KD/Twist1KDdouble knockdown cells were less efficient in establishing lung tumors thanBRMS1KDcells. Collectively, this study demonstrates that loss of BRMS1 promotes malignant phenotypes that are dependent on NF-κB-dependent regulation ofTwist1. These observations offer fresh insight into the mechanisms through which BRMS1 regulates the development of metastases in NSCLC.

scholarly journals Palladium nanoplates scotch breast cancer lung metastasis by constraining epithelial-mesenchymal transition

2020 ◽  
Author(s):  
Shunhao Wang ◽  
Jingchao Li ◽  
Mei Chen ◽  
Liting Ren ◽  
Wenya Feng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Metastasis ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Synergistic Effects ◽  
Cancer Therapeutics ◽  
Primary Tumors ◽  
Mesenchymal Transition

ABSTRACT Metastasis accounts for the majority of cancer deaths in many tumor types including breast cancer. Epithelial-mesenchymal transition (EMT) is the driving force for the occurrence and progression of metastasis, however, no targeted strategies to block the EMT program are currently available to combat metastasis. Diverse engineered nanomaterials (ENMs) have been reported to exert promising anti-cancer effects, however, no ENMs have been designed to target EMT. Palladium (Pd) nanomaterials, a type of ENM, have received substantial attention in nanomedicine due to their favorable photothermal performance for cancer therapeutics. Herein, Pd nanoplates (PdPL) were found to be preferentially biodistributed to both primary tumors and metastatic tumors. Importantly, PdPL showed a significant inhibition of lung metastasis with and without near-infrared (NIR) irradiation. Mechanistic investigations revealed that EMT was significantly compromised in breast cancer cells upon the PdPL treatment, which was partially due to the inhibition of the transforming growth factor-beta (TGF-β) signaling. Strikingly, the PdPL was found to directly interact with TGF-β proteins to diminish TGF-β functions in activating its downstream signaling, as evidenced by the reduced phosphorylation of Smad2. Notably, TGF-β-independent pathways were also involved in undermining EMT and other important biological processes that are necessary for metastasis. Additionally, NIR irradiation elicited synergistic effects on PdPL-induced inhibition of primary tumors and metastasis. In summary, these results revealed that the PdPL remarkably curbed metastasis by inhibiting EMT signaling, thereby indicating the promising potential of PdPL as a therapeutic agent for treating breast cancer metastasis.

scholarly journals Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1221 ◽  
Author(s):  
Brown ◽  
Marshall
Keyword(s):  
Transforming Growth Factor Beta ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Surveillance ◽  
Tumour Microenvironment ◽  
Mesenchymal Transition ◽  
Potential Benefits

TGFβ (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGFβ acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream signalling within the TGFβ pathway, and in established tumours, TGFβ then acts as a tumour promotor through multiple mechanisms including inducing epithelial-to-mesenchymal transition (EMT), promoting formation of cancer-associated fibroblasts (CAFs) and increasing angiogenesis. TGFβ is secrereted as a large latent complex and is embedded in the extracellular matrix or held on the surface of cells and must be activated before mediating its multiple functions. Thus, whilst TGFβ is abundant in the tumour microenvironment (TME), its functionality is regulated by local activation. The αv-integrins are major activators of latent-TGFβ. The potential benefits of manipulating the immune TME have been highlighted by the clinical success of immune-checkpoint inhibitors in a number of solid tumour types. TGFβ is a potent suppressor of T-cell-mediated immune surveillance and a key cause of resistance to checkpoint inhibitors. Therefore, as certain integrins locally activate TGFβ, they are likely to have a role in the immunosuppressive TME, although this remains to be confirmed. In this review, we discussed the role of TGFβ in cancer, the role of integrins in activating TGFβ in the TME, and the potential benefits of targeting integrins to augment immunotherapies.

scholarly journals Parthenolide Inhibits Migration and Reverses the EMT Process in Breast Cancer Cells by Suppressing TGFβ and TWIST1

2021 ◽  
Author(s):  
Hazera Binte Sufian ◽  
Julianna Maria Santos ◽  
Zeina Shreen Khan ◽  
Maliha Tabassum Munir ◽  
MD Khurshidul Zahid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Viability ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Breast Cancer Metastasis ◽  
Control Treatment ◽  
Mesenchymal Transition

Abstract Breast cancer metastasis is the leading cause of mortality among breast cancer patients. Epithelial to mesenchymal transition (EMT) is a biological process that plays a fundamental role in facilitating breast cancer metastasis. The present study assessed the efficacy of parthenolide (PTL,Tanacetum parthenium) on EMT and its underlying mechanisms in in both lowly metastatic, estrogen-receptor positive, MCF-7 cells and highly metastatic triple-negative MDA-MB-231 cells. Cell viability was determined by MTT (3-(4,5-dimethy lthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Apoptosis was analyzed by FITC (fluorescein isothiocyanate) annexin V apoptosis detection kit. The monolayer wound scratch assay was employed to evaluate cancer cell migration. Proteins were separated and identified by Western blotting. Gene expression was analyzed by quantitative real-time PCR. PTL treatment significantly reduced cell viability and migration while inducing apoptosis in both cell lines. Also, PTL treatment reverses the EMT process by decreasing the mesenchymal marker vimentin and increasing the epithelial marker E-cadherin compared to the control treatment. Importantly, PTL downregulates TWIST1 (a transcription factor and regulator of EMT) gene expression concomitant with the reduction of transforming growth factor beta (TGFβ) protein and gene expression in both cell lines. Our findings provide insights into the therapeutic potential of PTL to mitigate EMT and breast cancer metastasis. These promising results demand in vivo studies.

scholarly journals The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1

Open Biology ◽  
2013 ◽  
Vol 3 (6) ◽  
pp. 130067 ◽  
Author(s):  
Gopal P. Sapkota
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Phosphorylation ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein

The signalling pathways downstream of the transforming growth factor beta (TGFβ) family of cytokines play critical roles in all aspects of cellular homeostasis. The phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in TGFβ-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFβ cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFβ-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFβ-induced phosphorylation and activation of p38 MAPK in MEFs and HaCaT keratinocytes. Instead, RNAi -mediated depletion of MAP3K4 and MAP3K10 results in the inhibition of the TGFβ-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFβ-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFβ-induced activation of p38 MAPK.

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