Targeting cancer stem cell propagation with palbociclib, a CDK4/6 inhibitor: Telomerase drives tumor cell heterogeneity.
AffiliationPaterson Building, University of Manchester, Manchester M20 4BX
MetadataShow full item record
AbstractIn this report, we systematically examined the role of telomerase activity in lung and ovarian cancer stem cell (CSC) propagation. For this purpose, we indirectly gauged telomerase activity, by linking the hTERT-promoter to eGFP. Using lung (A549) and ovarian (SKOV3) cancer cells, transduced with the hTERT-GFP reporter, we then employed GFP-expression levels to fractionate these cell lines into GFP-high and GFP-low populations. We functionally compared the phenotype of these GFP-high and GFP-low populations. More specifically, we now show that the cancer cells with higher telomerase activity (GFP-high) are more energetically activated, with increased mitochondrial mass and function, as well as increased glycolytic activity. This was further validated and confirmed by unbiased proteomics analysis. Cells with high telomerase activity also showed an increased capacity for stem cell activity (as measured using the 3D-spheroid assay) and cell migration (as measured using a Boyden chamber approach). These enhanced biological phenotypes were effectively inhibited by classical modulators of energy metabolism, which target either i) mitochondrial metabolism (i.e., oligomycin) or ii) glycolysis (i.e., 2-deoxy-glucose), or iii) by using the FDA-approved antibiotic doxycycline, which inhibits mitochondrial biogenesis. Finally, the level of telomerase activity also determined the ability of hTERT-high cells to proliferate, as assessed by measuring DNA synthesis via EdU incorporation. Consistent with these observations, treatment with an FDA-approved CDK4/6 inhibitor (PD-0332991/palbociclib) specifically blocked the propagation of both lung and ovarian CSCs. Virtually identical results were obtained with breast CSCs, which were also highly sensitive to palbociclib at concentrations in the nanomolar range. In summary, CSCs with high telomerase activity are among the most energetically activated, migratory and proliferative cell sub-populations. These observations may provide a mechanistic explanation for tumor metabolic heterogeneity, based on telomerase activity. FDA-approved drugs, such as doxycycline and palbociclib, were both effective at curtailing CSC propagation. Thus, these FDA-approved drugs could be used to target telomerase-high proliferative CSCs, in multiple cancer types. Finally, our experiments also allowed us to distinguish two different cellular populations of hTERT-high cells, one that was proliferative (i.e., replicative immortality) and the other that was non-proliferative (i.e., quiescent). We speculate that the non-proliferative population of hTERT-high cells that we identified could be mechanistically involved in tumor dormancy.
CitationTargeting cancer stem cell propagation with palbociclib, a CDK4/6 inhibitor: Telomerase drives tumor cell heterogeneity. 2016 Oncotarget
- Dissecting tumor metabolic heterogeneity: Telomerase and large cell size metabolically define a sub-population of stem-like, mitochondrial-rich, cancer cells.
- Authors: Lamb R, Ozsvari B, Bonuccelli G, Smith DL, Pestell RG, Martinez-Outschoorn UE, Clarke RB, Sotgia F, Lisanti MP
- Issue date: 2015 Sep 8
- Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature.
- Authors: Knudsen ES, Hutcheson J, Vail P, Witkiewicz AK
- Issue date: 2017 Jul 4
- Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer.
- Authors: Sumi NJ, Kuenzi BM, Knezevic CE, Remsing Rix LL, Rix U
- Issue date: 2015 Dec 18
- Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells.
- Authors: De Luca A, Fiorillo M, Peiris-Pagès M, Ozsvari B, Smith DL, Sanchez-Alvarez R, Martinez-Outschoorn UE, Cappello AR, Pezzi V, Lisanti MP, Sotgia F
- Issue date: 2015 Jun 20
- Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer.
- Authors: Asghar US, Barr AR, Cutts R, Beaney M, Babina I, Sampath D, Giltnane J, Lacap JA, Crocker L, Young A, Pearson A, Herrera-Abreu MT, Bakal C, Turner NC
- Issue date: 2017 Sep 15