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

Abstract The secreted phospholipase A 2 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 PLA 2 -α activation and prostaglandin E 2 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.