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.

Activity of MM-398, Nanoliposomal Irinotecan (nal-IRI), in Ewing's Family Tumor Xenografts Is Associated with High Exposure of Tumor to Drug and High SLFN11 Expression

“…High expression of the putative DNA/RNA helicase SLFN11 has been recently reported to correlate with sensitivity to DNA damaging agents (20,21). We observed that sensitivity to DNA damaging agents (4-HC: active metabolite of cyclophosphamide, topotecan, SN-38), as determined by the DIMSCAN cytotoxicity assay, showed a significant correlation with SLFN11 expression assessed by the Affymetrix Human Exon Array in 17 EFT cell lines [ Supplementary Fig.…”

“…The mRNA expression of SLFN11, a putative RNA/DNA helicase, has been reported to correlate with the sensitivity to DNA damaging agents in the NCI60 panel of cell lines (21) or with the sensitivity to irinotecan in three EFT cell lines (20). Consistent with the previous report by Barretina and colleagues showing highest expression of SLFN11 in EFT primary samples among various cancer types (20), we found that SLFN11 mRNA expression was significantly higher (>100-fold) in EFT cell lines relative to NB and RMS cell lines (Fig.…”

“…High expression of SLFN11 has been reported for Ewing's family of tumors (20), and SLFN11 expression has been associated with sensitivity to cytotoxic agents (21). Therefore, we also examined the correlation between in vitro activity of SN-38 and SLFN11 expression in panels of pediatric cancer cell lines, the relative expression of SLFN11 in pediatric primary tumors, and the correlation of SLFN11 expression with the Ewing's-specific aberrant transcription factor EWS/FLI (22).…”

Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study

“…42,43 SLFN11, a member of the SLFN family, potently and specifically abrogates the production of retroviruses, e.g., human immunodeficiency virus (HIV-1). 33 Using cells with endogenously high and low SLFN11 expression and siRNA-mediated silencing, Zoppoli et al 44 found that SLFN11 causally determines cell death and cell cycle arrest in response to DNA-damaging agents in cancer cells from different tissues of origin. SLFN11 cg10911913 is located in a region whose function is promoter associated.…”

Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer

“…Other factors, acting either alone or in combination with proteins such as ABCB1, have been implicated in doxorubicin resistance through the downregulation of either Topo II or other DNA damage response (DDR) pathway constituents (7,8). Thus far, none of the above factors have been shown to individually account for the observed variability in patients' responses to doxorubicin (1,9). Taken together, the findings reported to date suggest the existence of other as of yet undefined molecular determinants instrumental in the conversion to a doxorubicin-resistant state.…”