scholarly journals hTERT Downregulation Attenuates Resistance to DOX, Impairs FAK-Mediated Adhesion, and Leads to Autophagy Induction in Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 867
Author(s):  
Aleksandra Romaniuk-Drapała ◽  
Ewa Totoń ◽  
Natalia Konieczna ◽  
Marta Machnik ◽  
Wojciech Barczak ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Therapeutic Potential ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Population Doubling ◽  
Cell Cycle Distribution ◽  
Human Telomerase Reverse Transcriptase ◽  
Human Telomerase

Telomerase is known to contribute to telomere maintenance and to provide cancer cell immortality. However, numerous reports are showing that the function of the enzyme goes far beyond chromosome ends. The study aimed to explore how telomerase downregulation in MCF7 and MDA-MB-231 breast cancer cells affects their ability to survive. Consequently, sensitivity to drug resistance, proliferation, and adhesion were assessed. The lentiviral-mediated human telomerase reverse transcriptase (hTERT) downregulation efficiency was performed at gene expression and protein level using qPCR and Western blot, respectively. Telomerase activity was evaluated using the Telomeric Repeat Amplification Protocol (TRAP) assay. The study revealed that hTERT downregulation led to an increased sensitivity of breast cancer cells to doxorubicin which was demonstrated in MTT and clonogenic assays. During a long-term doubling time assessment, a decreased population doubling level was observed. Interestingly, it did not dramatically affect cell cycle distribution. hTERT downregulation was accompanied by an alteration in β1-integrin- and by focal adhesion kinase (FAK)-driven pathways together with the reduction of target proteins phosphorylation, i.e., paxillin and c-Src. Additionally, autophagy activation was observed in MDA-MB-231 cells manifested by alternations in Atg5, Beclin 1, LC3II/I ratio, and p62. These results provide new evidence supporting the possible therapeutic potential of telomerase downregulation leading to induction of autophagy and cancer cells elimination.

scholarly journals Hyperoside Induces Breast Cancer Cells Apoptosis via ROS-Mediated NF-κB Signaling Pathway

2019 ◽  
Vol 21 (1) ◽  
pp. 131 ◽  
Author(s):  
Jinxia Qiu ◽  
Tao Zhang ◽  
Xinying Zhu ◽  
Chao Yang ◽  
Yaxing Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
B Cell Lymphoma ◽  
Flavonoid Glycosides

Hyperoside (quercetin 3-o-β-d-galactopyranoside) is one of the flavonoid glycosides with anti-inflammatory, antidepressant, and anti-cancer effects. But it remains unknown whether it had effects on breast cancer. Here, different concentrations of hyperoside were used to explore its therapeutic potential in both breast cancer cells and subcutaneous homotransplant mouse model. CCK-8 and wound healing assays showed that the viability and migration capability of Michigan Cancer Foundation-7 (MCF-7) and 4T1 cells were inhibited by hyperoside, while the apoptosis of cells were increased. Real-time quantitative PCR (qRT-PCR) and western blot analysis were used to detect mRNA and the protein level, respectively, which showed decreased levels of B cell lymphoma-2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and increased levels of Bax and cleaved caspase-3. After exploration of the potential mechanism, we found that reactive oxygen species (ROS) production was reduced by the administration of hyperoside, which subsequently inhibited the activation of NF-κB signaling pathway. Tumor volume was significantly decreased in subcutaneous homotransplant mouse model in hyperoside-treated group, which was consistent with our study in vitro. These results indicated that hyperoside acted as an anticancer drug through ROS-related apoptosis and its mechanism included activation of the Bax–caspase-3 axis and the inhibition of the NF-κB signaling pathway.

C/EBPδ Modulates Cell Growth, Differentiation and Apoptosis of Myeloid Leukemia, Prostate and Breast Cancer Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4300-4300
Author(s):  
Sigal Gery ◽  
Sakae Stanosaki ◽  
Takayuki Ikezoe ◽  
Wolf K. Hofmann ◽  
Adrian F. Gombart ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Myeloid Leukemia ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Leukemic Cells ◽  
Granulocytic Differentiation ◽  
Mcf 7

Abstract C/EBPδ belongs to the family of highly conserved CCAAT/enhancer binding protein (C/EBP) transcription factors. Members of this family play a critical role in the regulation of mitotic growth arrest and differentiation in numerous cell types. To examine the consequences of C/EPBδ expression, we transfected C/EPBδ into CML myeloid leukemia (KCL22, K562), prostate (LNCaP, PC3, DU145), and breast (MCF-7, T47D, MDA-MB-231) cancer cell lines. C/EBPδ expression resulted in a proliferative arrest and an increase in apoptosis of the myeloid leukemia cells, as well as the prostate cells LNCaP and PC3, and the breast cells MCF-7 and T47D. In contrast, DU145 prostate and MDA-MB-231 breast cancer cells were not inhibited by C/EBPδ, indicating that the biologically properties of C/EBPδ depend upon its cellular context. We further studied the molecular mechanisms underlying the affect of C/EPBδ expression in CML leukemic cells. Myeloid differentiation of KCL22 and K562 blast cells as shown by morphologic changes and induction of secondary specific granule genes, occurred within 4 days of inducing expression of C/EBPδ. Furthermore, expression of C/EBPδ was associated with downregulation of c-Myc and cyclin E, and upregulation of the forkhead transcription factor FoxO1a (FKHR) and the cyclin-dependent kinase inhibitor p27Kip1. In addition, microarray analysis showed that C/EBPδ mRNA is upregulated during granulocytic differentiation of normal CD34+ bone marrow cells, suggesting that C/EBPδ is involved in lineage-specific differentiation. Taken together, these results show that expression of C/EBPδ in BCR-ABL-positive CML cells in blast crisis, is sufficient for neutrophil differentiation and suggest that ectopic induction of C/EBPδ in the blastic phase of CML, as well as in certain cases of prostate and breast cancers, may hold promising therapeutic potential.

Expression Profile and up-Regulation of Telomere-Associated Proteins In Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4050-4050
Author(s):  
Rafael Díaz de la Guardia ◽  
Carolina Elosua ◽  
Purificación Catalina ◽  
Brian A Walker ◽  
David C Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Telomere Length ◽  
Conflicts Of Interest ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Post Translational Modification ◽  
Human Telomerase Reverse Transcriptase ◽  
Immortal Cells ◽  
Human Telomerase

Abstract Abstract 4050 The role of the telomeres in the mechanisms of ageing and carcinogenesis has generated a considerable interest as a novel approach to the treatment of many cancers. Telomeres are nucleoproteins structures that protect the ends of eukaryotic chromosomes, which are particularly vulnerable due to progressive shortening in almost all dividing cells. The telomere length was observed as a critical factor in the initiation and progression of human cancers, and it is associated to chromosomal instability. Most immortal cells possess enzymatic activity of telomerase. This suggests that telomerase activity and telomere length maintenance may be required for unlimited cell proliferation, tumorigenesis, and protection, allowing the evasion of apoptosis in cancer development. The telomerase activity could also be regulated positively or negatively by post-trancriptional and/or post-translational modification of the enzyme without transcriptional up-regulation of human telomerase reverse transcriptase (hTERT) mRNA. In this work, we analyze the expression data of all genes involved in telomerase activity. Patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), multiple myeloma (MM) and plasma cell leukemia (PLC) were studied through gene expression profiling analysis (Human Genome U133 Plus 2.0 arrays, Affymetrix). We identify 21 deregulated genes, implicated directly in telomere length maintenance activity in clonal plasma cells compared with normal cells (20 up-regulated and 1 down-regulated). These genes are MYC, KRAS, HSPA9, RB1 and members of the families: Small nucleolar ribonucleoproteins (H/ACA snoRNPs), A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs), and 14-3 -3 family. In conclusion, the myeloma cells acquire the telomere maintenance capability without deregulation of the human telomerase RNA gene (hTERC) and hTERT gene expression. It is an alternative lengthening of telomeres mechanism that has effect in the regulation of the BAD activity in apoptosis. The mechanism is based on preventing the partially-denatured proteins from aggregating, telomere maintenance through the correct processing and intranuclear trafficking of hTERC, telomerase reactivation and telomere stabilization, and efficient accumulation of hTERT in the nucleus. Thus, the findings of this study may help to improve telomerase-based therapy for multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

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