Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells
Nobiletin is a polymethoxy flavonoid isolated from Citrus depressa and Citrus reticulata. It has been reported that nobiletin can suppress tumors. We primarily explored the antitumor effects of nobiletin and the associated potential mechanisms in ACHN and Caki-2 renal carcinoma cells. A CCK-8 assay...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-07-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00690/full |
| _version_ | 1828377308913729536 |
|---|---|
| author | Di Wei Geng Zhang Zheng Zhu Yu Zheng Fei Yan Chongxian Pan Zhiyong Wang Xian Li Fuli Wang Ping Meng Wanxiang Zheng Zhao Yan Dongsheng Zhai Zifan Lu Jianlin Yuan |
| author_facet | Di Wei Geng Zhang Zheng Zhu Yu Zheng Fei Yan Chongxian Pan Zhiyong Wang Xian Li Fuli Wang Ping Meng Wanxiang Zheng Zhao Yan Dongsheng Zhai Zifan Lu Jianlin Yuan |
| author_sort | Di Wei |
| collection | DOAJ |
| description | Nobiletin is a polymethoxy flavonoid isolated from Citrus depressa and Citrus reticulata. It has been reported that nobiletin can suppress tumors. We primarily explored the antitumor effects of nobiletin and the associated potential mechanisms in ACHN and Caki-2 renal carcinoma cells. A CCK-8 assay and cloning experiments were used to assess cell viability, and a transwell assay and scratch test were used to assess metastatic ability. The cell cycle was analyzed by flow cytometry, whereas apoptosis was analyzed using flow cytometry and a terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. Protein expression was examined by Western blot and immunofluorescence. Renal cancer cells were subcutaneously transplanted into nude mice for in vivo studies. The data showed that nobiletin administration significantly dose- and time-dependently suppressed renal cancer cell proliferation; moreover, nobiletin treatment induced cell cycle arrest in the G0/G1 phase and promoted apoptosis. Immunofluorescence analysis indicated that nobiletin decreased the nuclear localization of signal transducer and activator of transcription 3 (STAT3) and YY1-associated protein 1 (YY1AP1). Western blot showed that the levels of phosphorylated SRC, phosphorylated AKT serine/threonine kinase (AKT), and phosphorylated STAT3 were decreased, whereas that of phosphorylated YY1AP1 was increased. The results further showed that application of insulin-like growth factor 1 (IGF1) was able to reverse the nobiletin-induced changes in the levels of phosphorylated AKT, phosphorylated STAT3, and phosphorylated YY1AP1, and could also reverse the antitumor effects of nobiletin. The results of in vivo experiments showed that, compared to the control, tumor volume and weight were both reduced following nobiletin treatment. In conclusion, our study demonstrated that nobiletin can inhibit renal carcinoma cell viability and provides a novel therapeutic approach for the treatment of kidney cancer. |
| first_indexed | 2024-04-14T08:12:09Z |
| format | Article |
| id | doaj.art-c08fb4e6c4304f26b6b51a2c07e87cc3 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-14T08:12:09Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-c08fb4e6c4304f26b6b51a2c07e87cc32022-12-22T02:04:32ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-07-011010.3389/fphar.2019.00690452549Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma CellsDi Wei0Geng Zhang1Zheng Zhu2Yu Zheng3Fei Yan4Chongxian Pan5Zhiyong Wang6Xian Li7Fuli Wang8Ping Meng9Wanxiang Zheng10Zhao Yan11Dongsheng Zhai12Zifan Lu13Jianlin Yuan14Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDivision of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, CA, United StatesDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaDepartment of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaState Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi’an, ChinaState Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi’an, ChinaDepartment of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, ChinaNobiletin is a polymethoxy flavonoid isolated from Citrus depressa and Citrus reticulata. It has been reported that nobiletin can suppress tumors. We primarily explored the antitumor effects of nobiletin and the associated potential mechanisms in ACHN and Caki-2 renal carcinoma cells. A CCK-8 assay and cloning experiments were used to assess cell viability, and a transwell assay and scratch test were used to assess metastatic ability. The cell cycle was analyzed by flow cytometry, whereas apoptosis was analyzed using flow cytometry and a terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. Protein expression was examined by Western blot and immunofluorescence. Renal cancer cells were subcutaneously transplanted into nude mice for in vivo studies. The data showed that nobiletin administration significantly dose- and time-dependently suppressed renal cancer cell proliferation; moreover, nobiletin treatment induced cell cycle arrest in the G0/G1 phase and promoted apoptosis. Immunofluorescence analysis indicated that nobiletin decreased the nuclear localization of signal transducer and activator of transcription 3 (STAT3) and YY1-associated protein 1 (YY1AP1). Western blot showed that the levels of phosphorylated SRC, phosphorylated AKT serine/threonine kinase (AKT), and phosphorylated STAT3 were decreased, whereas that of phosphorylated YY1AP1 was increased. The results further showed that application of insulin-like growth factor 1 (IGF1) was able to reverse the nobiletin-induced changes in the levels of phosphorylated AKT, phosphorylated STAT3, and phosphorylated YY1AP1, and could also reverse the antitumor effects of nobiletin. The results of in vivo experiments showed that, compared to the control, tumor volume and weight were both reduced following nobiletin treatment. In conclusion, our study demonstrated that nobiletin can inhibit renal carcinoma cell viability and provides a novel therapeutic approach for the treatment of kidney cancer.https://www.frontiersin.org/article/10.3389/fphar.2019.00690/fullnobiletinrenal carcinoma cellsSRCAKTSTAT3YY1AP1 |
| spellingShingle | Di Wei Geng Zhang Zheng Zhu Yu Zheng Fei Yan Chongxian Pan Zhiyong Wang Xian Li Fuli Wang Ping Meng Wanxiang Zheng Zhao Yan Dongsheng Zhai Zifan Lu Jianlin Yuan Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells Frontiers in Pharmacology nobiletin renal carcinoma cells SRC AKT STAT3 YY1AP1 |
| title | Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells |
| title_full | Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells |
| title_fullStr | Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells |
| title_full_unstemmed | Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells |
| title_short | Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells |
| title_sort | nobiletin inhibits cell viability via the src akt stat3 yy1ap1 pathway in human renal carcinoma cells |
| topic | nobiletin renal carcinoma cells SRC AKT STAT3 YY1AP1 |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00690/full |
| work_keys_str_mv | AT diwei nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT gengzhang nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT zhengzhu nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT yuzheng nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT feiyan nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT chongxianpan nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT zhiyongwang nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT xianli nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT fuliwang nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT pingmeng nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT wanxiangzheng nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT zhaoyan nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT dongshengzhai nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT zifanlu nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells AT jianlinyuan nobiletininhibitscellviabilityviathesrcaktstat3yy1ap1pathwayinhumanrenalcarcinomacells |