Cell type-specific upregulation of NKG2D ligand MICA in response to APTO253.

Abstract

One of the most important targets for natural killer (NK) cell-mediated therapy is the induction of natural killer group 2D ligand (NKG2D-L) expression. APTO253 is a small molecule that selectively kills acute myeloid leukemia (AML) cells, and it has been reported that APTO253 can induce Krüppel-like factor 4 (KLF4) expression and downregulate c-MYC expression. Recently, we discovered a novel role of APTO253 in modulating the NK cell response by inducing surface expression of NKG2D-Ls, especially MHC class I polypeptide-related sequence A (MICA), in AML cells. In this study, we extended the research to validate the effect of APTO253 in other cancer cell lines and found that the enhanced expression of NKG2D-Ls in response to APTO253 is limited in a tumor cell-specific manner. Here, we show that MICA induction upon treatment with APTO253 not only varies between ovarian and pancreatic cancer cell lines but also differs in two ovarian cancer cell lines for an unknown reason. Additionally, our data suggest a link between the induced expression of MICA and the regulation of both, KLF4 and c-MYC, which might represent a mechanism underlying the induction of NKG2D-L expression upon treatment with APTO253. These results may contribute to the potential use of APTO253 as a treatment to improve tumor cell-mediated NK cell cytotoxicity in various cancers.