Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway
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 a...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/15/8761 |
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| author | Gyeongmi Kim Se-Kyeong Jang Yu Jin Kim Hyeon-Ok Jin Seunghee Bae Jungil Hong In-Chul Park Jae Ho Lee |
| author_facet | Gyeongmi Kim Se-Kyeong Jang Yu Jin Kim Hyeon-Ok Jin Seunghee Bae Jungil Hong In-Chul Park Jae Ho Lee |
| author_sort | Gyeongmi Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T05:19:54Z |
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| id | doaj.art-222750bcf53d49f7856c4331f2b3c4a3 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T05:19:54Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-222750bcf53d49f7856c4331f2b3c4a32023-12-03T12:41:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012315876110.3390/ijms23158761Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling PathwayGyeongmi Kim0Se-Kyeong Jang1Yu Jin Kim2Hyeon-Ok Jin3Seunghee Bae4Jungil Hong5In-Chul Park6Jae Ho Lee7Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, KoreaDivision of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, KoreaDivision of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, KoreaKIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, KoreaDepartment of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, KoreaDepartment of Food and Microbial Technology, Seoul Women’s University, 621 Hwarangro, Nowon-gu, Seoul 01797, KoreaDivision of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, KoreaDepartment of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, KoreaOvarian 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.https://www.mdpi.com/1422-0067/23/15/8761ovarian cancerchemoresistanceglutamine uptakemetabolic reprogrammingASCT2mTORC1 |
| spellingShingle | Gyeongmi Kim Se-Kyeong Jang Yu Jin Kim Hyeon-Ok Jin Seunghee Bae Jungil Hong In-Chul Park Jae Ho Lee Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway International Journal of Molecular Sciences ovarian cancer chemoresistance glutamine uptake metabolic reprogramming ASCT2 mTORC1 |
| title | Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway |
| title_full | Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway |
| title_fullStr | Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway |
| title_full_unstemmed | Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway |
| title_short | Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway |
| title_sort | inhibition of glutamine uptake resensitizes paclitaxel resistance in skov3 tr ovarian cancer cell via mtorc1 s6k signaling pathway |
| topic | ovarian cancer chemoresistance glutamine uptake metabolic reprogramming ASCT2 mTORC1 |
| url | https://www.mdpi.com/1422-0067/23/15/8761 |
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