scholarly journals Triple Isozyme Lactic Acid Dehydrogenase Inhibition in Fully Viable MDA-MB-231 Cells Induces Cytostatic Effects That Are Not Reversed by Exogenous Lactic Acid

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1751
Author(s):  
Elizabeth Mazzio ◽  
Nzinga Mack ◽  
Ramesh B. Badisa ◽  
Karam F. A. Soliman
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Lactic Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Malignant Tumors ◽  
Glycolytic Pathway ◽  
Mitochondrial Potential ◽  
Lactic Acid Dehydrogenase ◽  
Acid Dehydrogenase

A number of aggressive human malignant tumors are characterized by an intensified glycolytic rate, over-expression of lactic acid dehydrogenase A (LDHA), and subsequent lactate accumulation, all of which contribute toward an acidic peri-cellular immunosuppressive tumor microenvironment (TME). While recent focus has been directed at how to inhibit LDHA, it is now becoming clear that multiple isozymes of LDH must be simultaneously inhibited in order to fully suppress lactic acid and halt glycolysis. In this work we explore the biochemical and genomic consequences of an applied triple LDH isozyme inhibitor (A, B, and C) (GNE-140) in MDA-MB-231 triple-negative breast cancer cells (TNBC) cells. The findings confirm that GNE-140 does in fact, fully block the production of lactic acid, which also results in a block of glucose utilization and severe impedance of the glycolytic pathway. Without a fully functional glycolytic pathway, breast cancer cells continue to thrive, sustain viability, produce ample energy, and maintain mitochondrial potential (ΔΨM). The only observable negative consequence of GNE-140 in this work, was the attenuation of cell division, evident in both 2D and 3D cultures and occurring in fully viable cells. Of important note, the cytostatic effects were not reversed by the addition of exogenous (+) lactic acid. While the effects of GNE-140 on the whole transcriptome were mild (12 up-regulated differential expressed genes (DEGs); 77 down-regulated DEGs) out of the 48,226 evaluated, the down-regulated DEGS collectively centered around a loss of genes related to mitosis, cell cycle, GO/G1–G1/S transition, and DNA replication. These data were also observed with digital florescence cytometry and flow cytometry, both corroborating a G0/G1 phase blockage. In conclusion, the findings in this work suggest there is an unknown element linking LDH enzyme activity to cell cycle progression, and this factor is completely independent of lactic acid. The data also establish that complete inhibition of LDH in cancer cells is not a detriment to cell viability or basic production of energy.

scholarly journals Matrix degradation and cell proliferation are coupled to promote invasion and escape from an engineered human breast microtumor

2021 ◽  
Vol 13 (1) ◽  
pp. 17-29
Author(s):  
Emann M Rabie ◽  
Sherry X Zhang ◽  
Andreas P Kourouklis ◽  
A Nihan Kilinc ◽  
Allison K Simi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Type I ◽  
Matrix Degradation ◽  
Human Breast ◽  
Rate Of Invasion

Abstract Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

scholarly journals Mutant p53L194F Harboring Luminal-A Breast Cancer Cells Are Refractory to Apoptosis and Cell Cycle Arrest in Response to MortaparibPlus, a Multimodal Small Molecule Inhibitor

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3043
Author(s):  
Ahmed Elwakeel ◽  
Anissa Nofita Sari ◽  
Jaspreet Kaur Dhanjal ◽  
Hazna Noor Meidinna ◽  
Durai Sundar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Luminal A ◽  
Molecular Analyses ◽  
Cycle Arrest ◽  
Mcf 7

We previously performed a drug screening to identify a potential inhibitor of mortalin–p53 interaction. In four rounds of screenings based on the shift in mortalin immunostaining pattern from perinuclear to pan-cytoplasmic and nuclear enrichment of p53, we had identified MortaparibPlus (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) as a novel synthetic small molecule. In order to validate its activity and mechanism of action, we recruited Luminal-A breast cancer cells, MCF-7 (p53wild type) and T47D (p53L194F) and performed extensive biochemical and immunocytochemical analyses. Molecular analyses revealed that MortaparibPlus is capable of abrogating mortalin–p53 interaction in both MCF-7 and T47D cells. Intriguingly, upregulation of transcriptional activation function of p53 (as marked by upregulation of the p53 effector gene—p21WAF1—responsible for cell cycle arrest and apoptosis) was recorded only in MortaparibPlus-treated MCF-7 cells. On the other hand, MortaparibPlus-treated T47D cells exhibited hyperactivation of PARP1 (accumulation of PAR polymer and decrease in ATP levels) as a possible non-p53 tumor suppression program. However, these cells did not show full signs of either apoptosis or PAR-Thanatos. Molecular analyses attributed such a response to the inability of MortaparibPlus to disrupt the AIF–mortalin complexes; hence, AIF did not translocate to the nucleus to induce chromatinolysis and DNA degradation. These data suggested that the cancer cells possessing enriched levels of such complexes may not respond to MortaparibPlus. Taken together, we report the multimodal anticancer potential of MortaparibPlus that warrants further attention in laboratory and clinical studies.

scholarly journals Overexpression of β-Arrestins inhibits proliferation and motility in triple negative breast cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Saber Yari Bostanabad ◽  
Senem Noyan ◽  
Bala Gur Dedeoglu ◽  
Hakan Gurdal
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Cell Function ◽  
Expression Profiles ◽  
Tissue Samples ◽  
Expression Levels ◽  
Cell Cycle Genes

Abstractβ-Arrestins (βArrs) are intracellular signal regulating proteins. Their expression level varies in some cancers and they have a significant impact on cancer cell function. In general, the significance of βArrs in cancer research comes from studies examining GPCR signalling. Given the diversity of different GPCR signals in cancer cell regulation, contradictory results are inevitable regarding the role of βArrs. Our approach examines the direct influence of βArrs on cellular function and gene expression profiles by changing their expression levels in breast cancer cells, MDA-MB-231 and MDA-MB-468. Reducing expression of βArr1 or βArr2 tended to increase cell proliferation and invasion whereas increasing their expression levels inhibited them. The overexpression of βArrs caused cell cycle S-phase arrest and differential expression of cell cycle genes, CDC45, BUB1, CCNB1, CCNB2, CDKN2C and reduced HER3, IGF-1R, and Snail. Regarding to the clinical relevance of our results, low expression levels of βArr1 were inversely correlated with CDC45, BUB1, CCNB1, and CCNB2 genes compared to normal tissue samples while positively correlated with poorer prognosis in breast tumours. These results indicate that βArr1 and βArr2 are significantly involved in cell cycle and anticancer signalling pathways through their influence on cell cycle genes and HER3, IGF-1R, and Snail in TNBC cells.

Steroidal aromatase inhibitors inhibit growth of hormone-dependent breast cancer cells by inducing cell cycle arrest and apoptosis

APOPTOSIS ◽  
2013 ◽  
Vol 18 (11) ◽  
pp. 1426-1436 ◽  
Author(s):  
Cristina Amaral ◽  
Carla Varela ◽  
Margarida Borges ◽  
Elisiário Tavares da Silva ◽  
Fernanda M. F. Roleira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Aromatase Inhibitors ◽  
Breast Cancer Cells ◽  
Cycle Arrest ◽  
Steroidal Aromatase Inhibitors

scholarly journals Cardanol isolated from Thai Apis mellifera propolis induces cell cycle arrest and apoptosis of BT-474 breast cancer cells via p21 upregulation

2015 ◽  
Vol 23 (1) ◽  
Author(s):  
Sureerat Buahorm ◽  
Songchan Puthong ◽  
Tanapat Palaga ◽  
Kriengsak Lirdprapamongkol ◽  
Preecha Phuwapraisirisan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Apis Mellifera ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cycle Arrest
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