PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling
| Autor: | Patrick Steigemann, Saskia Klutzny, Luise Schulze, Joseph L. Regan, Anna Anurin, Martin Lange, Karsten Parczyk, Barbara Nicke |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Phenotypic screening Immunology Cell Population Aldehyde dehydrogenase Article Metastasis Small Molecule Libraries 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cancer stem cell Cell Line Tumor medicine Humans lcsh:QH573-671 education Wnt Signaling Pathway Cyclic Nucleotide Phosphodiesterases Type 5 education.field_of_study biology lcsh:Cytology Chemistry Wnt signaling pathway Cell Biology Aldehyde Dehydrogenase Phosphodiesterase 5 Inhibitors medicine.disease Cyclic AMP-Dependent Protein Kinases 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer cell Neoplastic Stem Cells biology.protein Cancer research Mastodynia Signal Transduction |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 9, Iss 2, Pp 1-15 (2018) |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-017-0202-5 |
| Popis: | Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDHhigh) can be quantified in a heterogeneous cell population. We confirmed high ALDH activity as surrogate marker for the CSC subpopulation in vitro and validated Wnt signaling as an essential factor for the maintenance of CSCs in SUM149 breast cancer cells. In a small molecule screen, we identified phosphodiesterase type 5 (PDE5) inhibition as potential strategy to target CSC maintenance and survival in multiple cancer cell lines. CSC elimination by PDE5 inhibition was not dependent on PKG signaling, and we suggest a novel mechanism in which PDE5 inhibition leads to elevated cGMP levels that stimulate cAMP/PKA signaling to eliminate CSCs. |
| Databáze: | OpenAIRE |
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