Modulatory Effect of Indoles on the Expression of miRNAs Regulating G1/S Cell Cycle Phase in Breast Cancer Cells

2020 ◽  
Vol 192 (4) ◽  
pp. 1208-1223 ◽  
Author(s):  
Sherien M. El-Daly ◽  
Amira M. Gamal-Eldeen ◽  
Shaimaa A. Gouhar ◽  
Mahmoud T. Abo-elfadl ◽  
Gamila El-Saeed
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Cycle Phase ◽  
Cycle Phase

scholarly journals Combination Therapy of CDK4/CDK6 Inhibitor Palbociclib and Irradiation in non-Malign and Malign Cells

2020 ◽  
Author(s):  
Tina Jost ◽  
Markus Hecht ◽  
Paula Kapfer ◽  
Lucie Heinzerling ◽  
Rainer Fietkau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Cell Cycle Distribution ◽  
Cell Culture Model ◽  
Culture Model ◽  
Primary Fibroblasts

Abstract Background: The CDK 4/6 kinase inhibitor palbociclib is approved for first line treatment of metastatic breast cancer in combination with hormonal therapy and investigated within clinical trials for melanoma. In metastatic disease frequently palliative radiation treatment is necessary. Due to recent findings of radiosensitizing effects of palbociclib in HNSCC and HCC, a possible influence of palbociclib on radiosensitivity was studied in malign and non-malign cells. Methods: Different tumor cells and primary fibroblasts were treated with palbociclib and ionizing radiation (IR) in 2D and 3D cell cultures. Clonogenic assays were performed to study the sensitizing effect of palbociclib on irradiation induced cytotoxicity. Apoptosis, necrosis and cell cycle distribution was analyzed by flow cytometry. Cell migration was studied with scratch assays. Results: The effect of irradiation on skin cancer cells could be slightly decreased by palbociclib in four out of eight cells comparing 2 Gy vs. 2 Gy + 1 µmol/L in the 2D cell culture model. The 3D cell culture model detected differences in cell death more sensitive than the 2D model. Necrosis was increased in primary fibroblasts (0.2 µmol/L + IR vs. IR; p = 0.0041), whereas apoptosis was decreased in skin cancer cells ICNI (0.2 µmol/L + IR vs. IR with p = 0.0005 // 2 µmol/L + IR vs. IR with p = 0.0072). Overall palbociclib attenuated radiation induced cell death in skin and breast cancer cells. In malign cells combination therapy seems to rise senescence in clonogenic assays, whereas healthy controls showed more cell death. Palbociclib did not influence cell cycle distribution in the fibroblasts but led to an accumulation of the tumor cells in G0/G1 cell cycle phase. Additionally, palbociclib decreased migration behavior of the malign and non-malign cells, but without influence on e-cadherin expression during inhibitor treatment.Conclusions: Palbociclib increases the radiosensitivity of primary fibroblasts. In cancer cells palbociclib seems to be radioprotective. This effect in cancer cells is probably based on the accumulation of cells in the less radiosensitive G0/G1 cell cycle phase. Further studies are needed to assess whether a combined therapy of palbociclib and radiation is appropriate.

scholarly journals Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells

2000 ◽  
Vol 20 (7) ◽  
pp. 2581-2591 ◽  
Author(s):  
Alexander Swarbrick ◽  
Christine S. L. Lee ◽  
Robert L. Sutherland ◽  
Elizabeth A. Musgrove
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Molecular Weight ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cyclin E ◽  
Cycle Phase ◽  
Cdk Inhibitor ◽  
Progestin Treatment

ABSTRACT The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. The long-term effect of progestins on T-47D breast cancer cells is inhibition of cellular proliferation. This is accompanied by decreased G1 cyclin-dependent kinase (CDK) activities, redistribution of the CDK inhibitor p27Kip1among these CDK complexes, and alterations in the elution profile of cyclin E-Cdk2 upon gel filtration chromatography, such that high-molecular-weight complexes predominate. This study aimed to determine the relative contribution of CDK inhibitors to these events. Following progestin treatment, the majority of cyclin E- and D-CDK complexes were bound to p27Kip1 and few were bound to p21Cip1. In vitro, recombinant His6-p27 could quantitatively reproduce the effects on cyclin E-Cdk2 kinase activity and the shift in molecular weight observed following progestin treatment. In contrast, cyclin D-Cdk4 was not inhibited by His6-p27 in vitro or p27Kip1 in vivo. However, an increase in the expression of the Cdk4/6 inhibitor p18INK4c and its extensive association with Cdk4 and Cdk6 were apparent following progestin treatment. Recombinant p18INK4c led to the reassortment of cyclin-CDK-CDK inhibitor complexes in vitro, with consequent decrease in cyclin E-Cdk2 activity. These results suggest a concerted model of progestin action whereby p27Kip1 and p18INK4c cooperate to inhibit cyclin E-Cdk2 and Cdk4. Since similar models have been developed for growth inhibition by transforming growth factor β and during adipogenesis, interaction between the Cip/Kip and INK4 families of inhibitors may be a common theme in physiological growth arrest and differentiation.

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
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