# Targeting secreted PLA2 interactions with EGFR and vimentin to arrest prostate tumour growth

## TL;DR

Researchers developed cyclic peptides that inhibit hGIIA interactions, slowing prostate cancer growth and showing promise as a new treatment.

## Contribution

The study introduces cyclic peptides cF and c2 that inhibit hGIIA's protein-protein interactions, offering a novel therapeutic approach for prostate cancer.

## Key findings

- Cyclic peptides cF and c2 inhibit hGIIA interactions with EGFR and vimentin, reducing tumor growth.
- c2 blocks hGIIA-induced prostaglandin E2 production and promotes apoptosis in prostate cancer cells.
- The peptides are effective in multiple prostate cancer models at low doses and are non-toxic and orally bioavailable.

## Abstract

The secreted phospholipase A2 human group IIA (hGIIA) is overexpressed in prostate cancer (PCa), where its expression is closely aligned with malignancy. While its enzymatic activity is important in mediating innate immunity, here we highlight that hGIIA contributes to PCa pathology primarily through specific protein-protein interactions. We have developed cyclic peptides cF and c2, derived from the structure of hGIIA, that selectively inhibit these interactions and inhibit PCa growth. hGIIA interacts directly with epidermal growth factor receptor (EGFR), resulting in increased cytosolic PLA2-α activation and prostaglandin E2 production, which is suppressed by c2. Further, vimentin was identified to bind hGIIA in PCa cells, modulating hGIIA intracellular trafficking. c2 binds vimentin, blocking this interaction and initiating vimentin-mediated aggresome formation and apoptosis even in the absence of hGIIA. cF and c2 suppress androgen-sensitive, castrate-resistant and androgen-independent models of tumour growth in vivo at doses as low as 0.1 mg/kg, are non-toxic, orally bioavailable and cell-permeable. Critically, as with hGIIA, EGFR and vimentin are also increasingly expressed as PCa develops, cF and c2 may represent a novel therapeutic option for incurable metastatic castrate resistant PCa. Our findings identify hGIIA as an innate immune effector that regulates both inflammation and PCa progression and describe a novel class of hGIIA protein-protein interaction inhibitor with therapeutic potential in PCa.