Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer
Ying Liu,1,* Ning Zhang,1,* Hanwen Zhang,1 Lijuan Wang,2 Yi Duan,1 Xiaolong Wang,1 Tong Chen,1 Yiran Liang,1 Yaming Li,1 Xiaojin Song,1 Chen Li,1 Dianwen Han,1 Bing Chen,2 Wenjing Zhao,2 Qifeng Yang1,2 1Department of Breast Surgery, Qilu Hospital of Shandong University, Ji’nan, Shandong, P...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2020-08-01
|
| Series: | Drug Design, Development and Therapy |
| Subjects: | |
| Online Access: | https://www.dovepress.com/fatostatin-in-combination-with-tamoxifen-induces-synergistic-inhibitio-peer-reviewed-article-DDDT |
| _version_ | 1828850272921714688 |
|---|---|
| author | Liu Y Zhang N Zhang H Wang L Duan Y Wang X Chen T Liang Y Li Y Song X Li C Han D Chen B Zhao W Yang Q |
| author_facet | Liu Y Zhang N Zhang H Wang L Duan Y Wang X Chen T Liang Y Li Y Song X Li C Han D Chen B Zhao W Yang Q |
| author_sort | Liu Y |
| collection | DOAJ |
| description | Ying Liu,1,* Ning Zhang,1,* Hanwen Zhang,1 Lijuan Wang,2 Yi Duan,1 Xiaolong Wang,1 Tong Chen,1 Yiran Liang,1 Yaming Li,1 Xiaojin Song,1 Chen Li,1 Dianwen Han,1 Bing Chen,2 Wenjing Zhao,2 Qifeng Yang1,2 1Department of Breast Surgery, Qilu Hospital of Shandong University, Ji’nan, Shandong, People’s Republic of China; 2Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji’nan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qifeng Yang Email qifengy_sdu@163.comBackground: Tamoxifen is the cornerstone of adjuvant therapy for hormone receptor-positive breast cancer. Despite its efficacy, limited drug sensitivity and endocrine resistance remain the important clinical challenges. The main objective of this study was to investigate fatostatin, which was found to sensitize breast cancer to the antitumour effect of tamoxifen both in vitro and in vivo.Methods: Fatostatin-induced ER degradation was detected by immunoprecipitation assay. The antitumour effect of fatostatin and tamoxifen on MCF-7 and T47D cells was assessed by MTT and colony forming assays. Cell cycle arrest was detected by flow cytometric analysis. Apoptosis was detected by annexin V/propidium iodide double staining and TUNEL assay. Autophagy was detected by MDC assay and acridine orange staining. Migration and invasion assays were performed using a Transwell system, and the efficacy of the synergistic use of fatostatin and tamoxifen in vivo was evaluated using an MCF-7 xenograft model in BALB/c nu/nu female mice.Results: The synergistic use of fatostatin and tamoxifen significantly suppressed cell viability and invasion, induced cell cycle arrest, and regulated apoptosis and autophagy in MCF-7 and T47D cell lines via PI3K-AKT-mTOR signalling. Additionally, the expression levels of Atg7/12/13, beclin and LC3B increased while p-mTOR and P62 expression levels decreased after treatment with fatostatin and tamoxifen. Tumor growth in the xenograft model was suppressed significantly with the synergistic treatment of fatostatin and tamoxifen.Conclusion: Fatostatin could induce ER degradation by K48-linked polyubiquitination, which was the key mechanism contributing to tamoxifen inhibition of PI3K-AKT-mTOR signalling in breast cancer. Fatostatin may have a promising clinical use for ER-positive breast cancer patients.Keywords: tamoxifen, fatostatin, oestrogen-positive breast cancer, polyubiquitination |
| first_indexed | 2024-12-12T23:08:27Z |
| format | Article |
| id | doaj.art-11cc2723265243c3bb5b6af387a21414 |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-12T23:08:27Z |
| publishDate | 2020-08-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-11cc2723265243c3bb5b6af387a214142022-12-22T00:08:38ZengDove Medical PressDrug Design, Development and Therapy1177-88812020-08-01Volume 143535354556659Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast CancerLiu YZhang NZhang HWang LDuan YWang XChen TLiang YLi YSong XLi CHan DChen BZhao WYang QYing Liu,1,* Ning Zhang,1,* Hanwen Zhang,1 Lijuan Wang,2 Yi Duan,1 Xiaolong Wang,1 Tong Chen,1 Yiran Liang,1 Yaming Li,1 Xiaojin Song,1 Chen Li,1 Dianwen Han,1 Bing Chen,2 Wenjing Zhao,2 Qifeng Yang1,2 1Department of Breast Surgery, Qilu Hospital of Shandong University, Ji’nan, Shandong, People’s Republic of China; 2Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji’nan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qifeng Yang Email qifengy_sdu@163.comBackground: Tamoxifen is the cornerstone of adjuvant therapy for hormone receptor-positive breast cancer. Despite its efficacy, limited drug sensitivity and endocrine resistance remain the important clinical challenges. The main objective of this study was to investigate fatostatin, which was found to sensitize breast cancer to the antitumour effect of tamoxifen both in vitro and in vivo.Methods: Fatostatin-induced ER degradation was detected by immunoprecipitation assay. The antitumour effect of fatostatin and tamoxifen on MCF-7 and T47D cells was assessed by MTT and colony forming assays. Cell cycle arrest was detected by flow cytometric analysis. Apoptosis was detected by annexin V/propidium iodide double staining and TUNEL assay. Autophagy was detected by MDC assay and acridine orange staining. Migration and invasion assays were performed using a Transwell system, and the efficacy of the synergistic use of fatostatin and tamoxifen in vivo was evaluated using an MCF-7 xenograft model in BALB/c nu/nu female mice.Results: The synergistic use of fatostatin and tamoxifen significantly suppressed cell viability and invasion, induced cell cycle arrest, and regulated apoptosis and autophagy in MCF-7 and T47D cell lines via PI3K-AKT-mTOR signalling. Additionally, the expression levels of Atg7/12/13, beclin and LC3B increased while p-mTOR and P62 expression levels decreased after treatment with fatostatin and tamoxifen. Tumor growth in the xenograft model was suppressed significantly with the synergistic treatment of fatostatin and tamoxifen.Conclusion: Fatostatin could induce ER degradation by K48-linked polyubiquitination, which was the key mechanism contributing to tamoxifen inhibition of PI3K-AKT-mTOR signalling in breast cancer. Fatostatin may have a promising clinical use for ER-positive breast cancer patients.Keywords: tamoxifen, fatostatin, oestrogen-positive breast cancer, polyubiquitinationhttps://www.dovepress.com/fatostatin-in-combination-with-tamoxifen-induces-synergistic-inhibitio-peer-reviewed-article-DDDTtamoxifenfatostatinoestrogen-positive breast cancerpolyubiquitination |
| spellingShingle | Liu Y Zhang N Zhang H Wang L Duan Y Wang X Chen T Liang Y Li Y Song X Li C Han D Chen B Zhao W Yang Q Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer Drug Design, Development and Therapy tamoxifen fatostatin oestrogen-positive breast cancer polyubiquitination |
| title | Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer |
| title_full | Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer |
| title_fullStr | Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer |
| title_full_unstemmed | Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer |
| title_short | Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer |
| title_sort | fatostatin in combination with tamoxifen induces synergistic inhibition in er positive breast cancer |
| topic | tamoxifen fatostatin oestrogen-positive breast cancer polyubiquitination |
| url | https://www.dovepress.com/fatostatin-in-combination-with-tamoxifen-induces-synergistic-inhibitio-peer-reviewed-article-DDDT |
| work_keys_str_mv | AT liuy fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT zhangn fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT zhangh fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT wangl fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT duany fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT wangx fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT chent fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT liangy fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT liy fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT songx fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT lic fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT hand fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT chenb fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT zhaow fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer AT yangq fatostatinincombinationwithtamoxifeninducessynergisticinhibitioninerpositivebreastcancer |