Abstract 3054: CD47 signaling regulates a DNA damage response pathway by suppressing the expression of Schlafen-11 (SLFN11)

Abstract

Abstract Schlafen-11 (SLFN11) expression was recently shown to determine the sensitivity of human cancer cells to DNA damaging agents including topoisomerase inhibitors, DNA alkylating agents, and DNA synthesis inhibitors. High expression of SLFN11 in cancer cell lines results in increased sensitivity to these agents, whereas depletion of SLFN11 induces cellular protection. In addition, high expression of SHFN11 is associated with greater overall survival than low SLFN11 expression in ovarian patients treated with cisplatin. These observations suggest that SLFN11 may be an integral part of a critical DNA repair pathway. However, the pathways that regulate SLFN11 expression have not been reported. CD47 is an integrin-associated protein widely expressed on mammalian cells and frequently elevated in cancers. Its ligand, thrombospondin-1 (TSP1) induces CD47 signaling that regulates some growth factor receptors, cell fate, viability, and responses to cellular stresses such as radiation and chemotherapy. Our laboratory has previously shown that CD47 deficiency results in protection of nontransformed cells, whereas high CD47 expression sensitizes the same cells to ionizing radiation and DNA-damaging chemotherapy. We identified SLFN11 expression as a potential target of CD47 signaling by microarray analysis of a CD47-deficient mutant cell line and found that CD47 expression also correlates with that of SLFN11 in some human cancers. Thus, we sought to investigate the possible regulation of SLFN11 by CD47 by treating various cell lines with the function-modifying CD47 antibody B6H12 or its physiological ligands TSP1 and signal regulatory protein-α (SIRPα). qRT-PCR analysis revealed significant decreases in SLFN11 expression at 3 and 6 hours post-B6H12 treatment. Furthermore, treatment with TSP1 significantly decreased SHFN11 mRNA expression at the same time points, but SIRPα-Fc did not. Conversely, transient re-expression of CD47 in deficient cells elevated SLFN11 expression. These data demonstrate that pharmacological and physiological modulation of CD47 signaling acutely alters SLFN11 expression and suggests a potential mechanism by which CD47 modulates cellular sensitivity to DNA damaging chemotherapy agents. SLFN11 may in turn be a functional target and useful biomarker for the therapeutic CD47 antibodies currently in clinical trials. Citation Format: Anthony L. Schwartz, Sukhbir Kaur, Sai-Wen Tang, Yves Pommier, David D. Roberts. CD47 signaling regulates a DNA damage response pathway by suppressing the expression of Schlafen-11 (SLFN11). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3054.