Abstract 5488
Background
In the course of tumor growth, the cells that are far from the blood vessel are exposed to hypoxic conditions. As part of this process transcription factors (TFs) of the Snail family (Snail, Slug, Twist1, and Zeb1) are activated launching the epithelial-mesenchymal transition (EMT) program. Snail family factors are the most studied as stimulators of EMT, promoting tumor progression, migration and invasion of tumor cells. The aim of our research is to study adaptive mechanisms of human breast cancer (BC) cells to hypoxia and the analysis of the role of the TF Snail in this process.
Methods
We used human BC cells MCF-7, MDA-MB-231 and HBL-100 which were cultured in standard DMEM containing 10% fetal calf serum at 37oC and 5% СО2. For hypoxia modeling, the cells were cultured in a CO2-incubator maintaining O2 concentration at 1%.
Results
Knockdown of the Snail by small interfering RNA (siRNA) leads to increased sensitivity of breast cancer cells to hypoxia, due to increased blocking of cells in the S-phase of cell cycle. Cells were more resistant to hypoxia at a lower density, where Snail expression was increased, but further hyperexpression of Snail had not lead to increased resistance to hypoxia. Knockdown of Snail leads to an compensatory increase of Slug`s expression, while the knockdown of Twist1 and Zeb1 leads to decreased Slug expression. Knockdown of Twist1 decreases cell proliferation both in hypoxia and normoxia, through activation of cell cycle inhibitor p21WAF1, specifically in the G2/M phase, in p53-wild type HBL-100 cells. We used a chemical inhibitor of p53-Snail interaction GN25, to examine if blocking of this interaction could lead to increased sensitivity in hypoxia. We have shown that this compound has a greater cytotoxic effect in normoxia than hypoxia, due to increased Snail activity.
Conclusions
Modulation of Snail-associated signaling pathways is a perspective target for increase of cancer cell tolerance to chronic hypoxia, and inhibition of metastatic process in breast cancer cells.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Grant no. 14.W03.31.0020 between the Ministry of Science and Education of the Russian Federation and Institute of Gene Biology, Russian Academy of Sciences.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
592 - Effects of novel targeted anticancer drugs on cytotoxicity, apoptosis, angiogenesis, EMT, drug resistance and autophagic mechanism
Presenter: Seyma Aydinlik
Session: Poster Display session 1
Resources:
Abstract
3235 - Delineating the mechanisms of alpha 1-3 fucosyltransferase FUT11 in ovarian cancer
Presenter: Qi Chen
Session: Poster Display session 1
Resources:
Abstract
3577 - The tyrosine kinase inhibitor Dasatinib blocks tumor growth, invasion and recurrence potential by interrupting the communication between cancer cells and their surrounding microenvironment in triple negative breast cancer
Presenter: Miriam Nuncia-Cantarero
Session: Poster Display session 1
Resources:
Abstract
4808 - NORE1A induces a feedback termination of TNF signaling by antagonizing TNFR1 through ITCH-mediated destruction complex
Presenter: Jieun Ahn
Session: Poster Display session 1
Resources:
Abstract
1294 - Hsp90 inhibitors enhance the antitumoral effect of osimertinib and overcome osimertinib resistance in non-small-cell cell lung cancer cell models
Presenter: Jordi Codony-Servat
Session: Poster Display session 1
Resources:
Abstract
1559 - Expression of IL-17RA promotes cancer stem-like properties of colorectal cancer cells by Stat3 activation
Presenter: Chih-Yung Yang
Session: Poster Display session 1
Resources:
Abstract
1615 - Adaption of Pancreatic Cancer Cells to AKT1 Inhibition Induces the Acquisition of Cancer Stem-Cell Like Phenotype Through Upregulation of Mitochondrial Functions
Presenter: Hugo Arasanz
Session: Poster Display session 1
Resources:
Abstract
4793 - Bub3 is phosphorylated by the Ataxia-Telangiectasia Mutated Kinase in mitosis and required for activation of the mitotic spindle checkpoint in Breast Cancer
Presenter: Mingming Xiao
Session: Poster Display session 1
Resources:
Abstract
1448 - The regulation of INK4 locus by long non-coding RNAs
Presenter: Yojiro Kotake
Session: Poster Display session 1
Resources:
Abstract
1858 - Vascular Endothelial Growth Factor in Colorectal Cancer Pathology, Survival and Treatment
Presenter: Liz Baker
Session: Poster Display session 1
Resources:
Abstract