Cancer Migration and Invasion: Molecular Markers and Therapeutic Strategies

2024 | Vol-1 | Issue-1 | Date of Submission: | Date of Publication:

Abstract

In this presentation, progress in defining the role of two novel proteins, Annexin A2 and MIEN1, and therapeutic strategies against breast and prostate cancers, will be presented. Annexin A2 (AnxA2) is a plasma and endosomal membrane-associated protein. Its high levels have been correlated with poor distant metastasis-free survival and poor overall survival in triple negative breast cancer (TNBC) patients. It is also abundantly present in TEV and recruits TEV-associated cargo such as proteins and microRNAs. Migration and invasion enhancer 1 (MIEN1) is a candidate protein that is overexpressed in various cancers and plays an important role in cancer cell migration and invasion. Our lab reported that in vivo education with AnxA2 depleted EV led to reduced TNBC metastasis to lungs and brain suggesting a key role in the formation of a PMN. We used shRNA- mediated gene silencing to stably downregulate AnxA2 in organotropic TNBC cell lines derived from the parent MDA MB 231 cells. Differential ultracentrifugation was used to isolate EV from cell culture supernatant & size analysis was done using NTA. Upon depletion of AnxA2 protein, we observed a significant effect of AnxA2 depletion on its physiological role in plasmin generation. We observed a reduced yield of EV with AnxA2 depletion indicating a potential effect on EV biogenesis & release.Conserved regions of ITAM and prenylation motif in MIEN1 were used as a template to identify anti-cancer peptides. Two bioactive peptides (named LA3IK and RP-7) inhibited genes and proteins responsible for canghosh cer cell migration and invasion in both MDA-MB-231 breast cancer. RNA-seq, qPCR analysis and western blots showed changes in the transcriptome and protein expression after peptide treatment. The mechanism of the action of the peptides involves the inhibition of key pathways like Epithelial-Mesenchymal transition and Epidermal Growth Factor-mediated NF-κB pathway to exert their anti-cancer activity. Peptide treatments induced apoptosis in mice groups bearing tumors derived from MDA-MB-231 cells as evidenced by increased levels of cleaved caspase-3 and PARP proteins in western blots.