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FASEB J. 2017 Feb;31(2):625-635. doi: 10.1096/fj.201600953. Epub 2016 Oct 20.

Loss-of-function screens of druggable targetome against cancer stem-like cells.

Author information

1
Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Korea.
2
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Korea.
3
Environmental Risk and Welfare Research Team, Korea Basic Science Institute, Seoul, Korea.
4
Department of Biological Sciences, Sookmyung Women's University, Seoul, Korea.
5
College of Pharmacy, The Catholic University of Korea, Gyeonggi-do, Korea; and.
6
Systems Biology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas, USA.
7
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, Korea; wykim@sookmyung.ac.kr.
8
Center for Advanced Bioinformatics and Systems Medicine, Sookmyung Women's University, Seoul, Korea; yoonsj@sookmyung.ac.kr.

Abstract

Cancer stem-like cells (CSLCs) contribute to the initiation and recurrence of tumors and to their resistance to conventional therapies. In this study, small interfering RNA (siRNA)-based screening of ∼4800 druggable genes in 3-dimensional CSLC cultures in comparison to 2-dimensional bulk cultures of U87 glioma cells revealed 3 groups of genes essential for the following: survival of the CSLC population only, bulk-cultured population only, or both populations. While diverse biologic processes were associated with siRNAs reducing the bulk-cultured population, CSLC-eliminating siRNAs were enriched in a few functional categories, such as lipid metabolism, protein metabolism, and gene expression. Interestingly, siRNAs that selectively reduced CSLC only were found to target genes for cholesterol and unsaturated fatty acid synthesis. The lipidomic profile of CSLCs revealed increased levels of monounsaturated lipids. Pharmacologic blockage of these target pathways reduced CSLCs, and this effect was eliminated by addition of downstream metabolite products. The present CSLC-sensitive target categories provide a useful resource that can be exploited for the selective elimination of CSLCs.-Song, M., Lee, H., Nam, M.-H., Jeong, E., Kim, S., Hong, Y., Kim, N., Yim, H. Y., Yoo, Y.-J., Kim, J. S., Kim, J.-S., Cho, Y.-Y., Mills, G. B., Kim, W.-Y., Yoon, S. Loss-of-function screens of druggable targetome against cancer stem-like cells.

KEYWORDS:

CSLC sphere culture; lipid profile; network analysis; siRNA screening

PMID:
27811063
PMCID:
PMC5240669
DOI:
10.1096/fj.201600953
[Indexed for MEDLINE]
Free PMC Article

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