A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER− cells via endoplasmic reticulum stress-induced apoptosis
Abstract Tamoxifen (TAM) is the frontline therapy for estrogen receptor-positive (ER+) breast cancer in premenopausal women that interrupts ER signaling. As tumors with elevated heterogeneity, amounts of ER-negative (ER−) cells are present in ER+ breast cancer that cannot be directly killed by TAM....
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06539-3 |
| _version_ | 1797273039142912000 |
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| author | Tinglin Yang Wenhui Li Jun Zhou Ming Xu Ziwei Huang Jie Ming Tao Huang |
| author_facet | Tinglin Yang Wenhui Li Jun Zhou Ming Xu Ziwei Huang Jie Ming Tao Huang |
| author_sort | Tinglin Yang |
| collection | DOAJ |
| description | Abstract Tamoxifen (TAM) is the frontline therapy for estrogen receptor-positive (ER+) breast cancer in premenopausal women that interrupts ER signaling. As tumors with elevated heterogeneity, amounts of ER-negative (ER−) cells are present in ER+ breast cancer that cannot be directly killed by TAM. Despite complete remissions have been achieved in clinical practice, the mechanism underlying the elimination of ER− cells during TAM treatment remains an open issue. Herein, we deciphered the elimination of ER− cells in TAM treatment from the perspective of the bystander effect. Markable reductions were observed in tumorigenesis of ER− breast cancer cells by applying both supernatants from TAM-treated ER+ cells and a transwell co-culture system, validating the presence of a TAM-induced bystander effect. The major antitumor protein derived from ER+ cells, peptidyl-prolyl cis-trans isomerase B (PPIB), is the mediator of the TAM-induced bystander effect identified by quantitative proteomics. The attenuation of ER− cells was attributed to activated BiP/eIF2α/CHOP axis and promoted endoplasmic reticulum stress (ERS)-induced apoptosis, which can also be triggered by PPIB independently. Altogether, our study revealed a novel TAM-induced bystander effect in TAM treatment of ER+ breast cancer, raising the possibility of developing PPIB as a synergistic antitumor agent or even substitute endocrine therapy. |
| first_indexed | 2024-03-07T14:37:50Z |
| format | Article |
| id | doaj.art-73b089170e8b495fb90ae0cb759b52eb |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:37:50Z |
| publishDate | 2024-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-73b089170e8b495fb90ae0cb759b52eb2024-03-05T20:31:06ZengNature Publishing GroupCell Death and Disease2041-48892024-02-0115211410.1038/s41419-024-06539-3A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER− cells via endoplasmic reticulum stress-induced apoptosisTinglin Yang0Wenhui Li1Jun Zhou2Ming Xu3Ziwei Huang4Jie Ming5Tao Huang6Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Tamoxifen (TAM) is the frontline therapy for estrogen receptor-positive (ER+) breast cancer in premenopausal women that interrupts ER signaling. As tumors with elevated heterogeneity, amounts of ER-negative (ER−) cells are present in ER+ breast cancer that cannot be directly killed by TAM. Despite complete remissions have been achieved in clinical practice, the mechanism underlying the elimination of ER− cells during TAM treatment remains an open issue. Herein, we deciphered the elimination of ER− cells in TAM treatment from the perspective of the bystander effect. Markable reductions were observed in tumorigenesis of ER− breast cancer cells by applying both supernatants from TAM-treated ER+ cells and a transwell co-culture system, validating the presence of a TAM-induced bystander effect. The major antitumor protein derived from ER+ cells, peptidyl-prolyl cis-trans isomerase B (PPIB), is the mediator of the TAM-induced bystander effect identified by quantitative proteomics. The attenuation of ER− cells was attributed to activated BiP/eIF2α/CHOP axis and promoted endoplasmic reticulum stress (ERS)-induced apoptosis, which can also be triggered by PPIB independently. Altogether, our study revealed a novel TAM-induced bystander effect in TAM treatment of ER+ breast cancer, raising the possibility of developing PPIB as a synergistic antitumor agent or even substitute endocrine therapy.https://doi.org/10.1038/s41419-024-06539-3 |
| spellingShingle | Tinglin Yang Wenhui Li Jun Zhou Ming Xu Ziwei Huang Jie Ming Tao Huang A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER− cells via endoplasmic reticulum stress-induced apoptosis Cell Death and Disease |
| title | A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER− cells via endoplasmic reticulum stress-induced apoptosis |
| title_full | A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER− cells via endoplasmic reticulum stress-induced apoptosis |
| title_fullStr | A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER− cells via endoplasmic reticulum stress-induced apoptosis |
| title_full_unstemmed | A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER− cells via endoplasmic reticulum stress-induced apoptosis |
| title_short | A novel bystander effect in tamoxifen treatment: PPIB derived from ER+ cells attenuates ER− cells via endoplasmic reticulum stress-induced apoptosis |
| title_sort | novel bystander effect in tamoxifen treatment ppib derived from er cells attenuates er cells via endoplasmic reticulum stress induced apoptosis |
| url | https://doi.org/10.1038/s41419-024-06539-3 |
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