Purpose: This study aims to understand the role Angelica gigas (A. gigas) Nakai root extract (AGNRE) fermented with Jeju lava seawater in collagenase suppression in human dermal fibroblasts, and identify the major active compound responsible for it suppressive effect. Methods: AGNREs were prepared by fermentation with Jeju lava water at low temperature and analyzed for identifying the major active compound in these fermented root extracts using high-performance liquid chromatography (HPLC). Water-soluble tetrazolium salt (WST-1) assay and real-time polymerase chain reaction (qRT-PCR) were performed to investigate the cell viability and expression level of collagenase gene. Comparative experiments were performed using AGNREs and decursin to confirm the downregulation of collagenase expression and analyze the correlation between them. Results: HPLC analysis revealed decursin to be the major active compound in AGNREs. Analysis of data obtained by WST-1 assays at concentration of 200 μg/mL for AGNREs and <20 μM for decursin did not show any cytotoxicity in human dermal fibroblasts. qRT-PCR analysis revealed that AGNREs as well as decursin downregulated the expression of matrix metalloproteinases-3 (MMP3) gene in human dermal fibroblasts. Conclusion: These analyses suggest that AGNREs fermented with Jeju lava water as well as decursin isolated from these extracts hold a great potential to be applied as functional anti-wrinkle agent in cosmetic.

Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.

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