Schlafen-11 sensitizes colorectal carcinoma cells to irinotecan

Tian, Li; Song, Santai; Liu, Xiaojing; Wang, Yan; Xu, Xiaoguang; Hu, Yi; Xu, Jianming

doi:10.1097/cad.0000000000000151

Cited by 49 publications

(47 citation statements)

References 14 publications

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“…In addition, SLFN11 was recently discovered as a dominant response factor of cancer cells to topoisomerase I inhibitors (4, 5). Knockdown of SLFN11 increases chemoresistance of cancer cells to a broad range of DNA damaging agents (4, 6), and ectopic expression of SLFN11 sensitizes colon cancer cells to topoisomerase I inhibitors (7), consistent with the involvement of SLFN11 in the DNA damage response (4). Concurrently, David and coworkers demonstrated an anti-human immunodeficiency virus-1 (HIV-1) function of SLFN11 due to replication inhibition by selective suppression of viral protein synthesis in a codon-usage-dependent manner (8).…”

Section: Introductionmentioning

confidence: 70%

“…Because SLFN11 expression sensitizes cells to DNA damaging agents (4, 5, 7), we tested the impact of EWS-FLI1-mediated SLFN11 expression on the sensitivity of ES cells to camptothecin, a specific topoisomerase I inhibitor whose derivatives irinotecan and topotecan are widely used in the anticancer armamentarium (31). We found that doxycycline-induced EWS-FLI1 down-regulaton significantly reduced the sensitivity of ASP14 cells to camptothecin (IC 50 = 94 nM vs. 17 nM in the presence and absence of doxycycline, respectively; Fig.…”

Section: Resultsmentioning

confidence: 99%

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SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma

Tang¹,

Bilke

Cao

et al. 2015

Clinical Cancer Research

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Purpose SLFN11 was identified as a critical determinant of response to DNA targeted therapies by analyzing gene expression and drug sensitivity of NCI-60 and CCLE datasets. However, how SLFN11 is regulated in cancer cells remained unknown. Ewing’s sarcoma (ES), which is characterized by the chimeric transcription factor EWS-FLI1, has notably high SLFN11 expression, leading us to investigate whether EWS-FLI1 drives SLFN11 expression and the role of SLFN11 in the drug response of ES cells. Experimental Design Binding sites of EWS-FLI1 on the SLFN11 promoter were analyzed by chromatin immunoprecipitation-DNA sequence (ChIP-Seq) and promoter-luciferase reporter analyses. The relationship between SLFN11 and EWS-FLI1 were further examined in EWS-FLI1-knockdown or -overexpressing cells and in clinical tumor samples. Results EWS-FLI1 binds near the transcription start site of SLFN11 promoter and acts as a positive regulator of SLFN11 expression in ES cells. EWS-FLI1-mediated SLFN11 expression is responsible for high sensitivity of ES to camptothecin and combinations of PARP inhibitors with temozolomide. Importantly, ES patients with higher SLFN11 expression showed better tumor-free survival rate. The correlated expression between SLFN11 and FLI1 extends to leukemia, pediatric, colon, breast and prostate cancers. In addition, expression of other ETS members correlates with SLFN11 in NCI-60 and CCLE datasets, and molecular experiments demonstrate that ETS1 acts as a positive regulator for SLFN11 expression in breast cancer cells. Conclusions Our results imply the emerging relevance of SLFN11 as an ETS transcription factor response gene and for therapeutic response to topoisomerase I inhibitors and temozolomide-PARP inhibitor combinations in ETS-activated cancers.

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Section: Introductionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma

Tang¹,

Bilke

Cao

et al. 2015

Clinical Cancer Research

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“…Human SLFN11 has been shown to inhibit viral protein synthesis in HIV-infected cells (32) and to sensitize malignant cells to DNA-damaging agents and other chemotherapeutic cells (15). Human SLFN5 has been implicated in the control of anchorage-independent growth of malignant melanoma cells (18), while human SLFN12 has been im- plicated in the control of differentiation of prostate epithelial cells (13).…”

Section: Discussionmentioning

confidence: 99%

“…There are several human and mouse genes that are members of the SLFN family (9, 11). Prior evidence has implicated members of the Schlafen family in the regulation of tumorigenesis (13)(14)(15)(16)(17)(18). Notably, expression of various members of this family is upregulated following treatment with type I IFNs (17-19), cytokines known to promote induction of antineoplastic, antiviral, and immunoregulatory effects (1-4).…”

mentioning

confidence: 99%

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells

Sassano

Mavrommatis

Arslan

et al. 2015

Molecular and Cellular Biology

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We provide evidence that human SLFN5, an interferon (IFN)-inducible member of the Schlafen (SLFN) family of proteins, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of the matrix metalloproteinase 1 gene (MMP-1), MMP-13, and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 expression correlates with a better overall survival in a large cohort of patients with RCC. The inverse relationship between SLFN5 expression and RCC aggressiveness raises the possibility of developing unique therapeutic approaches in the treatment of RCC, by modulating SLFN5 expression. Interferons (IFNs) are cytokines with important antineoplastic activities and therefore are frequently utilized in the treatment of cancer (1-4). A malignancy that exhibits sensitivity to interferon treatment is renal cell carcinoma (RCC) (5). RCC is the most common type of kidney tumor in humans and is associated with high morbidity and mortality (6, 7). In general, patients with recurrent or advanced disease have limited treatment options and a very poor overall prognosis (7). The Schlafen (SLFN) family of genes includes several members that share structural homology and play regulatory roles in the control of cell cycle progression and cell growth arrest (8-12). There are several human and mouse genes that are members of the SLFN family (9, 11). Prior evidence has implicated members of the Schlafen family in the regulation of tumorigenesis (13)(14)(15)(16)(17)(18). Notably, expression of various members of this family is upregulated following treatment with type I IFNs (17-19), cytokines known to promote induction of antineoplastic, antiviral, and immunoregulatory effects (1-4). Despite the induction of human and mouse SLFN genes by IFNs, the precise mechanisms by which SLFNs mediate antineoplastic responses in different types of malignant human cells remain to be determined.In the present study, we provide evidence that the expression of human SLFN5 is inducible by type I IFN receptor. SLFN5, like other long SLFNs, is characterized by a large C-terminal extension, a DNA/RNA helicase domain, and a nuclear localization sequence (NLS) (9, 20). Although SLFN5 is induced in melanoma cells following IFN treatment (18), the role of SLFN5 in tumor progression is largely unknown.In efforts to define the functional implications of SLFN5 expression in malignant RCC cells, we found that SLFN5 repressed the motility and invasiveness of malignant renal cell carcinoma cells, by negatively controlling the expression of matrix metalloproteinase (MMP) genes, such as MMP-1 and MMP-13. Importantly, analysis of SLFN5 mRNA expression in a large number of samples from a cohort of RCC patients demonstrated that SLFN5 expression correlates with better overall survival of RCC patients. Altogether, our studies for the first time establish a mechanism by which...

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“…Nucleolar RBPs were overrepresented (Supplemental Fig. S1I), including 20 RNA helicases, among which some had previous implications in the DDR, namely DDX5/p68 (Nicol et al 2013), DDX1 (Li et al 2008), SLFN11 (Zoppoli et al 2012;Tian et al 2014), and DDX3X (Sun et al 2013). We thus hypothesized that increased binding of ribosomal proteins and rRNA binders to poly(A) + RNA reflected the DNA damage-induced disruption of nucleoli (Rubbi and Milner 2003).…”

Section: Many Nucleolar Proteins Exhibit Increased Binding To Polyadementioning

confidence: 99%

DDX54 regulates transcriptome dynamics during DNA damage response

et al. 2017

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The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of post-transcriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins, including many nucleolar proteins, showed increased binding to poly(A) + RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to-early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well-defined class of pre-mRNAs that harbor introns with weak acceptor splice sites, as well as by proteinprotein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Because DDX54 promotes survival after exposure to IR, its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR.

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Schlafen-11 sensitizes colorectal carcinoma cells to irinotecan

Cited by 49 publications

References 14 publications

SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma

SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells

DDX54 regulates transcriptome dynamics during DNA damage response

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