Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors

Abstract

Knockdown or gene disruption of the ubiquitously expressed cell surface receptor CD47 protects non-malignant cells from genotoxic stress caused by ionizing radiation or cytotoxic chemotherapy but sensitizes tumors in an immune competent host to genotoxic stress. The selective radioprotection of non-malignant cells is mediated in part by enhanced autophagy and protection of anabolic metabolism pathways, but differential H2AX activation kinetics suggested that the DNA damage response is also CD47-dependent. A high throughput screen of drug sensitivities indicated that CD47 expression selectively sensitizes Jurkat T cells to inhibitors of topoisomerases, which are known targets of Schlafen-11 (SLFN11). CD47 mRNA expression positively correlated with schlafen-11 mRNA expression in a subset of human cancers but not the corresponding non-malignant tissues. CD47 mRNA expression was also negatively correlated with SLFN11 promoter methylation in some cancers. CD47 knockdown, gene disruption, or treatment with a CD47 function-blocking antibody decreased SLFN11 expression in Jurkat cells. The CD47 signaling ligand thrombospondin-1 also suppressed schlafen-11 expression in wild type but not CD47-deficient T cells. Re-expressing SLFN11 restored radiosensitivity to a CD47-deficient Jurkat cells. Disruption of CD47 in PC3 prostate cancer cells similarly decreased schlafen-11 expression and was associated with a CD47-dependent decrease in acetylation and increased methylation of histone H3 in the SLFN11 promoter region. The ability of histone deacetylase or topoisomerase inhibitors to induce SLFN11 expression in PC3 cells was lost when CD47 was targeted in these cells. Disrupting CD47 in PC3 cells increased resistance to etoposide but, in contrast to Jurkat cells, not to ionizing radiation. These data identify CD47 as a context-dependent regulator of SLFN11 expression and suggest an approach to improve radiotherapy and chemotherapy responses by combining with CD47-targeted therapeutics.

SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors

“…Schlafen-11 (SLFN11) is an emergent restriction factor against genomic instability acting by eliminating cells with replicative damage ( 1 – 6 ) and potentially acting as a tumor suppressor ( 6 , 7 ). SLFN11-expressing cancer cells are consistently hypersensitive to a broad range of chemotherapeutic drugs targeting DNA replication, including topoisomerase inhibitors, alkylating agents, DNA synthesis, and poly(ADP-ribose) polymerase (PARP) inhibitors compared to SLFN11-deficient cancer cells, which are chemoresistant ( 1 , 2 , 4 , 8 – 17 ). Profiling SLFN11 expression is being explored for patients to predict survival and guide therapeutic choice ( 8 , 13 , 18 – 24 ).…”

Functions of Thrombospondin-1 in the Tumor Microenvironment

“…Cells lacking CD47 exhibited more rapid repair of dsDNA strand breaks induced by ionizing radiation [ 217 ]. Faster repair of DNA damage is probably supported by the increased induction of anabolic pathways that generate the nucleotides we observed in CD47-deficient cells after exposure to ionizing radiation [ 200 ].…”

“…Faster repair of DNA damage is probably supported by the increased induction of anabolic pathways that generate the nucleotides we observed in CD47-deficient cells after exposure to ionizing radiation [ 200 ]. Furthermore, CD47 expression selectively sensitized Jurkat T cells to specific inhibitors of topoisomerases, which are known targets of schlafen-11 (SLFN11), and to class I histone deacetylase (HDAC) inhibitors [ 217 ]. SLFN11 expression in human cancers is positively correlated with sensitivity to genotoxic agents, including topoisomerase inhibitors [ 218 , 219 , 220 , 221 , 222 , 223 , 224 ].…”

“…CD47 mRNA expression is positively correlated with SLFN11 mRNA expression in a subset of human cancers but not in the corresponding nonmalignant tissues in TCGA [ 217 ]. CD47 knockdown, gene disruption, or treatment with a CD47 function-blocking antibody decreased SLFN11 expression in Jurkat cells.…”

Recent Advancements in CD47 Signal Transduction Pathways Involved in Vascular Diseases

“…Consequently, CD47 antibody research and the use of its inhibitors can provide new targets for the treatment of various diseases. Interruption of CD47 signal conduction also repairs cell damage caused by ionizing radiation through enhanced autophagy, stem cell self-renewal, and metabolic pathways, to avoid the normal tissue damage [58]. In osteoarthritis, CD47/integrin α V β 3 also play an important role.…”