Dual Inhibition of IRE1α and YAP Signaling as a Potential Therapy for Epithelial Ovarian Carcinoma
<p>Epithelial ovarian carcinoma (EOC) is a highly lethal gynecological malignancy with limited treatment options. This study aimed to explore the regulatory roles of IRE1&alpha; and YAP1 in EOC progression and identify potential therapeutic targets. Blood and tissue samples were collected from 26 EOC patients and 10 patients with ovarian cysts. The expression of inflammatory factors in the blood was measured using ELISA. The proliferation, migration, invasion, and cell cycle of human ovarian cancer cell lines SK-OV-3, SW626, and Anglene were evaluated using MTT assays, scratch tests, Transwell assays, and flow cytometry. The effects of IRE1&alpha; inhibition on EOC cell proliferation, migration, and apoptosis were investigated using pharmacological inhibitors and shRNA knockdown. IRE1&alpha; was highly expressed in EOC patients and was negatively correlated with patient survival rates. Additionally, IRE1&alpha; scores in EOC patients were positively correlated with serum levels of TNF-&alpha; and VEGF-a. Compared to normal controls, significantly higher expressions of IRE1&alpha; and XBP1 were observed in ovarian cancer tissues and cells. Knockdown of IRE1&alpha; in ovarian cancer cells led to a significant reduction in the expression of IRE1&alpha; and XBP1s, as well as inhibited cell proliferation and survival. The IRE1&alpha; inhibitors STF-083100 and 4&mu;8C suppressed the proliferation, invasion, and migration of SK-OV-3 cells and reduced the expression levels of related factors. 4&mu;8C inhibited the degradation of YAP within SK-OV-3 cells while downregulating the expression of Cyclin D1 protein. Compared to the group treated with 4&mu;8C alone, the combined intervention of 4&mu;8C and a YAP inhibitor showed a more pronounced inhibitory effect on the proliferation of SK-OV-3 cells.This study first reveals that the IRE1&alpha;/YAP signal drives the malignant progression of EOC through the regulation of cell proliferation, migration, and invasion. The dual-targeted synergistic inhibition of IRE1&alpha;/YAP1 offers an innovative therapeutic paradigm for the treatment of EOC.
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