A small molecule (pluripotin) as a tool for studying cancer stem cell biology: proof of concept.

Abstract

BACKGROUND:

Cancer stem cells (CSC) are thought to be responsible for tumor maintenance and heterogeneity. Bona fide CSC purified from tumor biopsies are limited in supply and this hampers study of CSC biology. Furthermore, purified stem-like CSC subpopulations from existing tumor lines are unstable in culture. Finding a means to overcome these technical challenges would be a useful goal. In a first effort towards this, we examined whether a chemical probe that promotes survival of murine embryonic stem cells without added exogenous factors can alter functional characteristics in extant tumor lines in a fashion consistent with a CSC phenotype.

METHODOLOGY/PRINCIPAL FINDINGS:

The seven tumor lines of the NCI60 colon subpanel were exposed to SC-1 (pluripotin), a dual kinase and GTPase inhibitor that promotes self-renewal, and then examined for tumorigenicity under limiting dilution conditions and clonogenic activity in soft agar. A statistically significant increase in tumor formation following SC-1 treatment was observed (p<0.04). Cloning efficiencies and expression of putative CSC surface antigens (CD133 and CD44) were also increased. SC-1 treatment led to sphere formation in some colon tumor lines. Finally, SC-1 inhibited in vitro kinase activity of RSK2, and another RSK2 inhibitor increased colony formation implicating a role for this kinase in eliciting a CSC phenotype.

CONCLUSIONS/SIGNIFICANCE:

These findings validate a proof of concept study exposure of extant tumor lines to a small molecule may provide a tractable in vitro model for understanding CSC biology.

• Authors: Susan D Mertins, Dominic A Scudiero, Melinda G Hollingshead, Raymond D Divelbiss Jr, Michael C Alley, Anne Monks, David G Covell, Karen M Hite, David S Salomon, John E Niederhuber
• Journal: PloS one (PLoS One) Vol. 8 Issue 2 Pg. e57099 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23437320 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Biomarkers
• Octamer Transcription Factor-3
• Pyrazoles
• Pyrimidines
• SC1 compound
• Ribosomal Protein S6 Kinases, 90-kDa
• ribosomal protein S6 kinase, 90kDa, polypeptide 3
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Biomarkers (metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Humans
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Neoplastic Stem Cells (drug effects, metabolism)
• Octamer Transcription Factor-3 (metabolism)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Ribosomal Protein S6 Kinases, 90-kDa (antagonists & inhibitors, metabolism)
• Spheroids, Cellular (drug effects)
• Transplantation, Heterologous
• Tumor Burden (drug effects)
• Tumor Cells, Cultured
• Tumor Stem Cell Assay