Jin-Hyung Kim

FRY Mediates THP1-Driven Ovarian Cancer Invasion Through the PI3K/AKT Pathway

Ovarian cancer remains the most lethal gynecological malignancy, largely due to its early dissemination and extensive peritoneal metastasis. The tumor microenvironment (TME), particularly tumor-associated macrophages, promotes this invasive phenotype; however, the precise molecular effectors linking immune-to-tumor signaling remain unclear. We identified FRY, a microtubule-binding protein previously uncharacterized in ovarian pathology, as a critical mediator of macrophage-driven invasion. We observed that conditioned medium from ovarian cancer-stimulated macrophages (OCM) robustly induced FRY expression in ovarian cancer cells. Clinically, elevated FRY levels correlate with advanced tumor stage and poor patient survival. Functionally, FRY knockdown significantly abrogated OCM-induced invasion without affecting cell viability, highlighting its specific role in motility. Mechanistically, FRY facilitates epithelial–mesenchymal transition (EMT) and acts as an essential downstream effector of the PI3K/AKT signaling cascade; notably, FRY was required for AKT1-driven invasive behaviors. Furthermore, we identified the transcription factor NFIX as a key regulator of FRY expression. Macrophage-derived signals upregulate NFIX, which directly regulates FRY transcription. Pharmacological inhibition of the CXCR1/2 axis with reparixin effectively blocked OCM-mediated induction of both NFIX and FRY, suggesting that chemokine signaling initiates this pro-invasive loop. Collectively, these findings suggest that FRY is a macrophage-driven mediator of invasion and underscore its potential relevance in ovarian cancer.

Enhanced Expression of TRIM46 in Ovarian Cancer Cells Induced by Tumor-Associated Macrophages Promotes Invasion via the Wnt/β-Catenin Pathway

Metastasis presents significant challenges in ovarian cancer treatment. Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) facilitate metastasis through epithelial-mesenchymal transition, yet the molecular underlying mechanisms are not fully understood. Here, we identified that tripartite motif-containing 46 (TRIM46) is significantly upregulated in ovarian cancer cells treated with a conditioned medium derived from macrophages stimulated by ovarian cancer cells (OC-MQs). Furthermore, TRIM46 was highly expressed in late-stage ovarian cancer patients and was associated with poor prognosis. Silencing of TRIM46 suppressed cancer cell invasion stimulated by OC-MQ and mesenchymal marker expression without affecting cell viability. Gene set enrichment analysis showed that the Wnt/β-catenin pathway is enriched in the high-TRIM46 expression group. Importantly, the inhibition of TRIM46-mediated β-catenin nuclear translocation and ovarian cancer cell invasion was reversed by CHIR99021, a Wnt/β-catenin activator. Additionally, C-X-C motif chemokine ligand 8 (CXCL8) was identified as being highly expressed in peritoneal MQs from the ascites of ovarian cancer patients and was positively correlated with C-X-C chemokine receptor 1/2 (CXCR1/2) expression in tumor cells. Notably, pre-treatment with reparixin, a CXCR1/2 inhibitor, blocked OC-MQ-induced TRIM46 expression and cell invasion. These results suggest that CXCL8 derived from TAMs promotes human ovarian cancer cell invasion via the Wnt/β-catenin pathway by upregulating TRIM46.

Marine Sponge-Derived Gukulenin A Sensitizes Ovarian Cancer Cells to PARP Inhibition via Ferroptosis Induction

Resistance to PARP inhibitors (PARPi), such as olaparib (OLA), is a major challenge in ovarian cancer treatment. In this study, we investigated the combination effect of PARPi and gukulenin A (GUA), a bis-tropolone tetraterpenoid isolated from the marine sponge Phorbas gukhulensis. We found that GUA at a mildly cytotoxic dose synergistically enhanced OLA-induced cytotoxicity in human ovarian cancer cells. The combination treatment significantly increased reactive oxygen species (ROS) levels and lipid peroxidation, leading to ferroptotic rather than apoptotic cell death. Network pharmacology and gene ontology (GO) enrichment analyses revealed oxidative stress-related pathways as key mediators of this effect. Inhibition of NADPH oxidase (NOX) reversed combination-induced cell death, while ferrostatin-1 (FER-1), a ferroptosis inhibitor, significantly reduced lipid peroxidation and cytotoxicity. Additionally, GUA and OLA treatment suppressed ERK1/2 activation, and ERK overexpression attenuated the combination-induced cell death. Collectively, these findings suggest that marine-derived GUA enhances PARPi efficacy in ovarian cancer cells by inducing ferroptosis through oxidative stress and ERK pathway modulation.