Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents.

Abstract

DNA-damaging agents (DDAs) constitute the backbone of treatment for most human tumors. Here we used the National Cancer Institute Antitumor Cell Line Panel (the NCI-60) to identify predictors of cancer cell response to topoisomerase I (Top1) inhibitors, a widely used class of DDAs. We assessed the NCI-60 transcriptome using Affymetrix Human Exon 1.0 ST microarrays and correlated the in vitro activity of four Top1 inhibitors with gene expression in the 60 cell lines. A single gene, Schlafen-11 (SLFN11), showed an extremely significant positive correlation with the response not only to Top1 inhibitors, but also to Top2 inhibitors, alkylating agents, and DNA synthesis inhibitors. Using cells with endogenously high and low SLFN11 expression and siRNA-mediated silencing, we show that SLFN11 is causative in determining cell death and cell cycle arrest in response to DDAs in cancer cells from different tissues of origin. We next analyzed SLFN11 expression in ovarian and colorectal cancers and normal corresponding tissues from The Cancer Genome Atlas database and observed that SLFN11 has a wide expression range. We also observed that high SLFN11 expression independently predicts overall survival in a group of ovarian cancer patients treated with cisplatin-containing regimens. We conclude that SLFN11 expression is causally associated with the activity of DDAs in cancer cells, has a broad expression range in colon and ovarian adenocarcinomas, and may behave as a biomarker for prediction of response to DDAs in the clinical setting.

• Authors: Gabriele Zoppoli, Marie Regairaz, Elisabetta Leo, William C Reinhold, Sudhir Varma, Alberto Ballestrero, James H Doroshow, Yves Pommier
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 37 Pg. 15030-5 (Sep 11 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22927417 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Nuclear Proteins
• SLFN11 protein, human
• Topoisomerase I Inhibitors
• DNA Helicases

Topics

• Cell Line, Tumor
• Colony-Forming Units Assay
• DNA Damage (drug effects)
• DNA Helicases (metabolism)
• Gene Expression Profiling
• Humans
• Immunoblotting
• Microarray Analysis
• Microscopy, Confocal
• Neoplasms (metabolism)
• Nuclear Proteins (metabolism)
• RNA Interference
• Topoisomerase I Inhibitors (pharmacology)