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Polyoxometalate inhibition of SOX2-mediated tamoxifen resistance in breast cancer.
- Source :
-
Cell communication and signaling : CCS [Cell Commun Signal] 2024 Sep 02; Vol. 22 (1), pp. 425. Date of Electronic Publication: 2024 Sep 02. - Publication Year :
- 2024
-
Abstract
- Background: Increased cancer stem cell (CSC) content and SOX2 overexpression are common features in the development of resistance to therapy in hormone-dependent breast cancer, which remains an important clinical challenge. SOX2 has potential as biomarker of resistance to treatment and as therapeutic target, but targeting transcription factors is also challenging. Here, we examine the potential inhibitory effect of different polyoxometalate (POM) derivatives on SOX2 transcription factor in tamoxifen-resistant breast cancer cells.<br />Methods: Various POM derivatives were synthesised and characterised by infrared spectra, powder X-ray diffraction pattern and nuclear magnetic resonance spectroscopy. Estrogen receptor (ER) positive breast cancer cells, and their counterparts, which have developed resistance to the hormone therapy tamoxifen, were treated with POMs and their consequences assessed by gel retardation and chromatin immunoprecipitation to determine SOX2 binding to DNA. Effects on proliferation, migration, invasion and tumorigenicity were monitored and quantified using microscopy, clone formation, transwell, wound healing assays, flow cytometry and in vivo chick chorioallantoic membrane (CAM) models. Generation of lentiviral stable gene silencing and gene knock-out using CRISPR-Cas9 genome editing were applied to validate the inhibitory effects of the selected POM. Cancer stem cell subpopulations were quantified by mammosphere formation assays, ALDEFLUOR activity and CD44/CD24 stainings. Flow cytometry and western blotting were used to measure reactive oxygen species (ROS) and apoptosis.<br />Results: POMs blocked in vitro binding activity of endogenous SOX2. [P <subscript>2</subscript> W <subscript>18</subscript> O <subscript>62</subscript> ] <superscript>6-</superscript> (PW) Wells-Dawson-type anion was the most effective at inhibiting proliferation in various cell line models of tamoxifen resistance. 10 µM PW also reduced cancer cell migration and invasion, as well as SNAI2 expression levels. Treatment of tamoxifen-resistant cells with PW impaired tumour formation by reducing CSC content, in a SOX2-dependent manner, which led to stem cell depletion in vivo. Mechanistically, PW induced formation of reactive oxygen species (ROS) and inhibited Bcl-2, leading to the death of tamoxifen-resistant cells. PW-treated tamoxifen-resistant cells showed restored sensitivity to tamoxifen.<br />Conclusions: Together, these observations highlight the potential use of PW as a SOX2 inhibitor and the therapeutic relevance of targeting SOX2 to treat tamoxifen-resistant breast cancer.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Female
Cell Proliferation drug effects
Cell Movement drug effects
Neoplastic Stem Cells drug effects
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Cell Line, Tumor
Animals
SOXB1 Transcription Factors metabolism
SOXB1 Transcription Factors genetics
Tamoxifen pharmacology
Breast Neoplasms pathology
Breast Neoplasms drug therapy
Breast Neoplasms genetics
Breast Neoplasms metabolism
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Tungsten Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1478-811X
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell communication and signaling : CCS
- Publication Type :
- Academic Journal
- Accession number :
- 39223652
- Full Text :
- https://doi.org/10.1186/s12964-024-01800-w