Abstract
Survival factors play critical roles in regulating cell growth in normal and cancer cells. We designed a genetic screen to identify survival factors which protect tumor cells from apoptosis. A retroviral expression library of random cDNA fragments was constructed from cancer cells and used to transduce the colon carcinoma cell line HCT116. Recipient cells were functionally selected for induction of caspase 3-mediated apoptosis. Analyses of over 10 000 putative genetic suppression elements (GSEs) sequences revealed cognate gene candidates that are implicated in apoptosis. We further analysed 26 genes encoding cell surface and secreted proteins that can potentially serve as targets for therapeutic antibodies. Tetracycline-inducible GSEs from several gene candidates induced apoptosis in stable HCT 116 cell lines. Similar phenotypes were caused by RNAi derived from the same genes. Our data suggest requirement for the cell surface targets IGF2R, L1CAM and SLC31A1 in tumor cell growth in vitro, and suggests that IGF2R is required for xenograft tumor growth in a mouse model.
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Acknowledgements
We thank Patrick O'Connor, Serge Lichtsteiner, Paul Rejto, Todd VanArsdale, Mike North, Stephen Bender and Stephen Dunn for critical review and discussions of the data, Jerry Barnhart for expert assistance with flow cytometry, Igor Roninson for a gift of pLNXCO3 vector, NCI for panel of tumor cell lines. Part of this work was carried out in collaboration with Pfizer, Inc. and Surromed, Inc.
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Gelman, M., Ye, X., Stull, R. et al. Identification of cell surface and secreted proteins essential for tumor cell survival using a genetic suppressor element screen. Oncogene 23, 8158–8170 (2004). https://doi.org/10.1038/sj.onc.1208054
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DOI: https://doi.org/10.1038/sj.onc.1208054
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