Roles of PKR in High Grade Serous Ovarian Cancer

High-grade serous ovarian carcinoma (HGSC) is characterized by dissemination within the peritoneal cavity, a process that critically depends on dynamic regulation of cell adhesion, migration, and invasion rather than primary tumor growth. Protein kinase R (PKR; EIF2AK2) is classically described as a stress-activated kinase within the integrated stress response (ISR); however, its role in ovarian cancer metastasis remains poorly defined. In this study, we investigated the functional contribution of PKR to HGSC progression using integrated in-vitro, in-vivo, and multi-omics approaches. Genetic depletion of PKR in HGSC cell lines resulted in marked impairment of migratory and invasive capacities, particularly under three-dimensional and extracellular matrix-engaging conditions. In-vivo, PKR-deficient cells exhibited reduced metastatic dissemination and delayed tumor progression in both immunodeficient and syngeneic mouse models. Proteomic analyses of ascites and tumor-derived samples revealed consistent enrichment of adhesion-, focal adhesion-, and extracellular matrix-related pathways, with convergence on integrin signaling, cytoskeletal organization, and matrix remodeling factors across models. Notably, the majority of shared deregulated proteins were adhesion-associated, underscoring a central role for PKR in regulating metastatic mechanics rather than proliferation or survival. Mechanistically, basal PKR phosphorylation and downstream ISR activation were not detected under steady-state conditions, and re-expression of kinase-dead PKR rescued the invasive defects observed in PKR-null cells, indicating that PKR potentially regulates HGSC invasion mostly through kinase-independent mechanisms. These findings suggest a structural or scaffolding role for PKR within adhesion-related signaling networks. Preliminary protein interaction and phosphoproteomic analyses further support the involvement of PKR in multi-protein complexes linked to cytoskeletal dynamics. Collectively, this work identifies PKR as a non-canonical regulator of adhesion-driven metastasis in HGSC and highlights functions of PKR as critical determinants of ovarian cancer dissemination.

Department dc:contributor.department

Biomedical and Molecular Sciences

Year dc:date.issued

2026

Author dc:creator

• Afzali, Farzaneh

Advisor dc:contributor.supervisor

• Postovit, Lynne-Marie

• ovarian_cancer
• PKR
• metastasis

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1974/36268

OAI identifier oai:identifier

oai:queensu.scholaris.ca:1974/36268