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

The secreted phospholipase A<sub>2</sub> 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<sub>2</sub>-α activation and prostaglandin E<sub>2</sub> 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.

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Publication Details

Journal
Cell Death and Disease
Published
2025-12-20
DOI
https://doi.org/10.1038/s41419-025-08280-x
Primary Topic
Cell Adhesion Molecules Research
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Garry G. Graham, Enrico Gratton, Paul de Souza, Qihan Dong et al.
Cell Death and Disease
Cell Adhesion Molecules Research
article

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

Garry G. Graham, Enrico Gratton, Paul de Souza, Qihan Dong, Anya Salih, Albert S. Mellick, Isabelle Meyer-Carrive, Jun Zeng, Vinod Kumar, Russell Pickford, Kieran F. Scott, David G. Harman, Nathan Main, Maria George Elias, Peter Galettis, Abdel Qader Al Bawab, Winston Liauw, Shadma Fatima, Mila Sajinovic, Timothy J. Mann, W. Bret Church, Ryung Rae Kim, Pamela J. Russell, Gregory J. Cooney, Edwin Huang, Hiba Bahidh
article en

Abstract

The secreted phospholipase A<sub>2</sub> 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<sub>2</sub>-α activation and prostaglandin E<sub>2</sub> 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.

Cell Death and DiseaseVol. 17(1)
University of Technology Sydney (AU), Camden and Campbelltown Hospitals (AU), The University of Sydney (AU), Al-Zaytoonah University of Jordan (JO), Queensland University of Technology (AU), The University of Queensland (AU), University of California, Irvine (US), IP Australia (AU), UNSW Sydney (AU), St Vincent's Hospital Sydney (AU), Bayer (Australia) (AU), St George Hospital (AU), Ingham Institute (AU), Medical Developments International (Australia) (AU), Western Sydney University (AU)
Prostate Cancer Foundation, St George and Sutherland Medical Research Foundation, Prostate Cancer Foundation of Australia, Rebecca L. Cooper Medical Research Foundation, Ingham Institute for Applied Medical Research, Western Sydney University, Medical Research Council, National Health and Medical Research Council
Openalex Percentile: Top 47%
Cell Adhesion Molecules Research
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