snx-2112 and Colorectal-Neoplasms

Colorectal cancer (CRC) is a global disease with high incidence and mortality rate. Hsp90 inhibitors induce cell death in various cancers, including CRC. However, the underlying mechanisms need to be clarified further. In this study, Caco-2 cells were treated with 0.25 μM SNX-2112, an Hsp90 inhibitor, for 48 h; subsequently, whole-transcriptome sequencing was performed. At the mRNA level in SNX-2112-treated Caco-2 cells, 1588 genes were upregulated, and 433 genes were downregulated. Six genes were found to be associated with necroptosis and apoptosis, and these 6 upregulated genes were validated by RT-qPCR. Hundred and six miRNAs were upregulated, and 48 miRNAs were downregulated in SNX-2112-treated Caco-2 cells. Eleven downregulated miRNAs were found to interact with the 6 upregulated genes. Moreover, 676 circRNAs were upregulated, and 291 circRNAs were downregulated in SNX-2112-treated Caco-2 cells. Among them, 126 circRNAs were found to be the target of the 11 downregulated miRNAs. The circRNA-miRNA-mRNA regulatory network of Hsp90 inhibitor-induced cell death in colorectal cancer was constructed. This regulatory network extends the underlying mechanism of Hsp90 and improves our understanding of Hsp90 inhibitors as potential targeted therapeutic agents.

Topics: Caco-2 Cells; Colonic Neoplasms; Colorectal Neoplasms; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Ontology; Gene Regulatory Networks; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; MicroRNAs; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; RNA; RNA, Circular; RNA, Messenger; Up-Regulation

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF cells and tissues exhibit various mitochondrial abnormalities. However, the underlying molecular mechanisms remain elusive. Here, we examined the mechanisms through which CFTR regulates Bcl-2 family proteins, which in turn regulate permeabilization of the mitochondrial outer membrane. Notably, inhibition of CFTR activated Bax and Bad, but inhibited Bcl-2. Moreover, degradation of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT increased significantly in CFTR-knockdown cells. Dysfunction of CFTR decreased heat-shock protein 90 (Hsp90) mRNA levels, and CFTR was found to interact with Hsp90. Inhibition of Hsp90 by SNX-2112 induced the degradation of phosphorylated AKT and ERK1/2 in Caco2 and HRT18 cells. These findings may help provide insights into the physiological role of CFTR in CF-related diseases.

Topics: bcl-2-Associated X Protein; bcl-Associated Death Protein; Caco-2 Cells; Colorectal Neoplasms; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Gene Knockdown Techniques; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; MAP Kinase Signaling System; Mitochondria; Phosphorylation; Proteolysis; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Transduction, Genetic; Up-Regulation