Hee Jung Kim

IL-6 Inhibitory Compounds from the Aerial Parts of Piper attenuatum and Their Anticancer Activities on Ovarian Cancer Cell Lines

Piper attenuatum Buch-Ham, a perennial woody vine belonging to the Piperaceae family, is traditionally used in Southeast Asia for treating various ailments such as malaria, headache, and hepatitis. This study described the isolation and identification of three new compounds, piperamides I-III (1–3), which belong to the maleimide-type alkaloid skeletons, along with fifteen known compounds (4–18) from the methanol extract of the aerial parts of P. attnuatum. Their chemical structures were elucidated using spectroscopic methods (UV, IR, ESI-Q-TOF-MS, and 1D/2D NMR). All the isolates were evaluated for their ability to inhibit IL-6 activity in the human embryonic kidney-Blue™ IL-6 cell line and their cytotoxic activity against ovarian cancer cell lines (SKOV3/SKOV3-TR) and chemotherapy-resistant variants (cisplatin-resistant A2780/paclitaxel-resistant SKOV3). The compounds 3, 4, 11, 12, 17, and 18 exhibited IL-6 inhibition comparable to that of the positive control bazedoxifene. Notably, compound 12 displayed the most potent anticancer effect against all the tested cancer cell lines. These findings highlight the importance of researching the diverse activities of both known and newly discovered natural products to fully unlock their potential therapeutic benefits.

E2F8 Induces Cell Proliferation and Invasion through the Epithelial–Mesenchymal Transition and Notch Signaling Pathways in Ovarian Cancer

Background: Despite the recent research implicating E2F8 (E2F Transcription Factor 8) in cancer, the role of E2F8 in the progression of ovarian cancer has remained unclear. Hence, we explored the bio-functional effects of E2F8 knockdown on ovarian cancer cell lines in vitro and in vivo. Methods: The expression of E2F8 was compared between ovarian cancer and noncancer tissues, and its association with the progression-free survival of ovarian cancer patients was analyzed. To demonstrate the function of E2F8 in cell proliferation, migration, and invasion, we employed RNA interference to suppress E2F8 expression in ovarian cancer cell lines. Finally, the effect of E2F8 knockdown was investigated in a xenograft mouse model of ovarian cancer. Results: Ovarian cancer tissue exhibited significantly higher E2F8 expression compared to that of normal ovarian tissue. Clinical data showed that E2F8 was a significant predictor of progression-free survival. Moreover, the prognosis of the ovarian cancer patients with high E2F8 expression was poorer than that of the patients with low E2F8 expression. In vitro experiments using E2F8-knockdown ovarian cancer cell lines demonstrated that E2F8 knockdown inhibited cell proliferation, migration, and tumor invasion. Additionally, E2F8 was a potent inducer and modulator of the expression of epithelial–mesenchymal transition and Notch signaling pathway-related markers. We confirmed the function of E2F8 in vivo, signifying that E2F8 knockdown was significantly correlated with reduced tumor size and weight. Conclusions: Our findings indicate that E2F8 is highly correlated with ovarian cancer progression. Hence, E2F8 can be utilized as a prognostic marker and therapeutic target against ovarian malignancy.

LncRNA SRA mediates cell migration, invasion, and progression of ovarian cancer via NOTCH signaling and epithelial–mesenchymal transition

Abstract Long non-coding RNA (lncRNA) is a newly identified regulator of tumor formation and tumor progression. The function and expression of lncRNAs remain to be fully elucidated, but recent studies have begun to address their importance in human health and disease. The lncRNA, SRA, known as steroid receptor activator, acts as an important modulator of gynecological cancer, and its expression may affect biological functions including proliferation, apoptosis, steroid formation, and muscle development. However, it is still not well known whether SRA is involved in the regulation of ovarian cancer. The present study investigated the molecular function and association between SRA expression and clinicopathological factors. In ovarian cancer cell lines, SRA knockdown and overexpression regulated cell migration, proliferation, and invasion. Both in vivo and in vitro experiments using knockdown and overexpression showed that SRA potently regulated epithelial–mesenchymal transition (EMT) and NOTCH pathway components. Further, clinical data confirmed that SRA was a significant predictor of overall survival (OS) and progression-free survival and patients with ovarian cancer exhibiting high expression of SRA exhibited higher recurrence rates than patients with low SRA expression. In conclusion, the present study indicates that SRA has clinical significance as its expression can predict the prognosis of ovarian cancer patients. High expression of the lncRNA SRA is strongly correlated with recurrence-free survival of ovarian cancer patients.

IA‐0130, a novel 3‐(1,3‐diarylallylidene)oxindole derivative, alleviates ovarian cancer via inhibiting IL‐6/gp130/STAT3 signalling

Background and Purpose Dysregulation of the IL‐6/glycoprotein 130(gp130)/STAT3 signalling axis is implicated in several human diseases, particularly cancer. Notably, gp130, a single transducer of this signalling axis, is a target for ovarian cancer treatment. However, data regarding small‐molecule inhibitors of gp130 are lacking. Therefore, we aimed to identify a 3‐(1,3‐diarylallylidene)oxindole derivative that binds gp130 and reveal the anticancer mechanism acting on the IL‐6/gp130/STAT3 pathway in ovarian cancer. Experimental Approach We synthesised 24 derivatives based on the scaffold of 3‐(1,3‐diarylallylidene)oxindole, and derivatives that inhibit IL‐6 signalling were selected using HEK‐Blue™ IL‐6 cells. The binding of derivatives to gp130 was assessed using surface plasmon resonance. IA‐0130, with a strong gp130‐binding ability, was selected to observe its effect on the migration, invasion, cell cycle arrest and apoptosis of ovarian cancer cells in comparison to bazedoxifene, a known gp130‐binding derivative. Additionally, we examined the mechanism underlying the tumour suppressive effect of IA‐0130 in vivo. Key Results We found that IA‐0130 inhibited gp130/STAT3 phosphorylation in a concentration‐dependent manner in ovarian cancer cell line and also in ovarian cancer‐resistant cell line. By suppressing the expression of downstream target genes, IA‐0130 inhibited cancer cell growth, metastasis, and invasion and induced apoptosis, exhibiting anticancer effects. In a mouse xenograft model of human ovarian cancer, oral administration of IA‐0130 significantly delayed tumour growth. Conclusions and Implications IA‐0130 inhibits tumour growth, migration and metastasis by inhibiting IL‐6/gp130/STAT3 signalling in ovarian cancer by binding gp130. IA‐0130 holds therapeutic potential for treating ovarian cancer as well as anticancer drug‐resistant ovarian cancer.