Inhibitory effect of VNLG-152R on breast cancer cells MDA-MB-231
In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on Triple Negative Breast Cancer (TNBC) cells both in vitro and in vivo. The TNBC cell line MDA-MB-231 cells were treated with VNLG-152R. A total of 337 genes were differentially expressed when MDA-MB-231 cells were treated with 10 µM VNLG-152R for 24h; 259 genes were upregulated and 78 downregulated. Through proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Overall design: Vehicle Control-DMSO in trplicates and VNLG-152R 10 µM, in triplicates; treatment duration-24 hours.