Transcriptome profiling of H295R adrenocortical carcinoma cells treated with the CK2/CLK inhibitor CX-4945 (silmitasertib)

ABSTRACT: Adrenocortical carcinoma is a rare and aggressive endocrine malignancy whose growth and hormonal output depend on the nuclear receptor NR5A1 (steroidogenic factor-1, SF-1), a transcription factor for which no ligand-based therapy is established. To ask whether the transcript rather than the protein can be targeted pharmacologically, H295R adrenocortical carcinoma cells were treated with the clinical CK2/CLK inhibitor CX-4945 (silmitasertib) and gene expression was profiled by microarray. CX-4945 induced two aberrant NR5A1 transcripts generated by skipping of consecutive internal exons, and reduced full-length NR5A1 protein, without altering NR5A1 promoter activity. Neither aberrant isoform transactivated the StAR promoter, and expression of NR5A1 target genes together with secreted cortisol and aldosterone fell accordingly. Functional annotation of the down-regulated transcripts returned terms related to alternative splicing. The dormancy-associated factor NR2F1 was among the down-regulated genes, and CX-4945 released the cells from G1. Loss of viability caused by the compound proceeded in cells that do not express NR5A1 and was accompanied by induction of endoplasmic reticulum stress markers and by extensive cytoplasmic vacuolation; the mode of cell death was not determined. These data describe a route to a nuclear receptor that has resisted direct pharmacological targeting, by redirecting the splicing of its transcript.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133197 | GEO | 2022/06/24

REPOSITORIES: GEO