Dpep Inhibits Cancer Cell Growth and Survival via Shared and Context-Dependent Transcriptome Perturbations

SIMPLE SUMMARY: Dpep is a novel cell-penetrating peptide that selectively promotes the death of multiple tumor cell types in vitro and in vivo, and that is a potential therapeutic option for cancer. To better understand how it kills cancer cells, we compared gene expression levels in each of six diverse cancer cell lines before and after peptide treatment. An analysis of the data suggested a mechanism in which Dpep initiates a cascade of perturbations in gene expression that are particular to each cancer cell type, but that represent shared pathways that regulate cell growth and survival. These findings provide insight as to how drugs such as Dpep are able to impact the survival of a wide variety of tumor cell types, and identify how it might be combined with other cancer drugs for optimal efficacy. ABSTRACT: Dpep is a cell-penetrating peptide targeting transcription factors ATF5, CEBPB, and CEBPD, and that selectively promotes the apoptotic death of multiple tumor cell types in vitro and in vivo. As such, it is a potential therapeutic. To better understand its mechanism of action, we used PLATE-seq to compare the transcriptomes of six cancer cell lines of diverse origins before and after Dpep exposure. This revealed a context-dependent pattern of regulated genes that was unique to each line, but that exhibited a number of elements that were shared with other lines. This included the upregulation of pro-apoptotic genes and tumor suppressors as well as the enrichment of genes associated with responses to hypoxia and interferons. Downregulated transcripts included oncogenes and dependency genes, as well as enriched genes associated with different phases of the cell cycle and with DNA repair. In each case, such changes have the potential to lie upstream of apoptotic cell death. We also detected the regulation of unique as well as shared sets of transcription factors in each line, suggesting that Dpep may initiate a cascade of transcriptional responses that culminate in cancer cell death. Such death thus appears to reflect context-dependent, yet shared, disruption of multiple cellular pathways as well as of individual survival-relevant genes.