TMEM45A enhances palbociclib resistance and cellular glycolysis by activating AKT/mTOR signaling pathway in HR+ breast cancer
Abstract Palbociclib, a CDK4/6 inhibitor, plays a crucial role in the treatment of HR+ breast cancer. However, resistance to palbociclib is a significant concern that merits further investigation. Our investigation identifies TMEM45A as a potential driver of palbociclib resistance and its associatio...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02336-9 |
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| author | Cui Chen Zehong Chen Jinze Zhao Xinyun Wen Hanming Yao Zijin Weng Huiping Xiong Zongheng Zheng Juekun Wu |
| author_facet | Cui Chen Zehong Chen Jinze Zhao Xinyun Wen Hanming Yao Zijin Weng Huiping Xiong Zongheng Zheng Juekun Wu |
| author_sort | Cui Chen |
| collection | DOAJ |
| description | Abstract Palbociclib, a CDK4/6 inhibitor, plays a crucial role in the treatment of HR+ breast cancer. However, resistance to palbociclib is a significant concern that merits further investigation. Our investigation identifies TMEM45A as a potential driver of palbociclib resistance and its association with increased cellular glycolysis. We demonstrate that TMEM45A is highly expressed in palbociclib-resistant breast cancer (BRCA) cells, correlating with enhanced tumor progression. Silencing TMEM45A enhances sensitivity to palbociclib, promotes cell cycle arrest and apoptosis, and inhibits the proliferation of BRCA cells. Moreover, attenuation of TMEM45A expression reduces cancer aggressiveness by decreasing the expression of EMT and glycolysis-related proteins. Subsequent gene set enrichment analysis (GSEA) confirms that TMEM45A activates the AKT/mTOR signaling pathway, which is integral to cell cycle progression and glycolysis. In a cell line-derived xenograft (CDX) mouse model, TMEM45A knockdown significantly restores sensitivity to palbociclib and suppresses tumor growth. Additionally, the use of engineered exosomes loaded with siRNA targeting TMEM45A presents a promising strategy for enhancing CDK4/6 inhibitor sensitivity without observable toxic side effects in a patient-derived xenograft (PDX) model. Collectively, our findings suggest that TMEM45A may be a therapeutic target for overcoming palbociclib resistance, and exosomal siRNA delivery could be a viable strategy for precision medicine in HR+ breast cancer. |
| format | Article |
| id | doaj-art-6c2707ad252349f589a7650943461f44 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-6c2707ad252349f589a7650943461f442025-02-09T12:12:34ZengNature Publishing GroupCell Death Discovery2058-77162025-02-0111111510.1038/s41420-025-02336-9TMEM45A enhances palbociclib resistance and cellular glycolysis by activating AKT/mTOR signaling pathway in HR+ breast cancerCui Chen0Zehong Chen1Jinze Zhao2Xinyun Wen3Hanming Yao4Zijin Weng5Huiping Xiong6Zongheng Zheng7Juekun Wu8Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Sun Yat-sen UniversityDepartment of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen UniversityDepartment of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Sun Yat-sen UniversityDepartment of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Sun Yat-sen UniversityDepartment of Gastroenterology, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical UniversityDepartment of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen UniversityDepartment of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Sun Yat-sen UniversityDepartment of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen UniversityDepartment of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Sun Yat-sen UniversityAbstract Palbociclib, a CDK4/6 inhibitor, plays a crucial role in the treatment of HR+ breast cancer. However, resistance to palbociclib is a significant concern that merits further investigation. Our investigation identifies TMEM45A as a potential driver of palbociclib resistance and its association with increased cellular glycolysis. We demonstrate that TMEM45A is highly expressed in palbociclib-resistant breast cancer (BRCA) cells, correlating with enhanced tumor progression. Silencing TMEM45A enhances sensitivity to palbociclib, promotes cell cycle arrest and apoptosis, and inhibits the proliferation of BRCA cells. Moreover, attenuation of TMEM45A expression reduces cancer aggressiveness by decreasing the expression of EMT and glycolysis-related proteins. Subsequent gene set enrichment analysis (GSEA) confirms that TMEM45A activates the AKT/mTOR signaling pathway, which is integral to cell cycle progression and glycolysis. In a cell line-derived xenograft (CDX) mouse model, TMEM45A knockdown significantly restores sensitivity to palbociclib and suppresses tumor growth. Additionally, the use of engineered exosomes loaded with siRNA targeting TMEM45A presents a promising strategy for enhancing CDK4/6 inhibitor sensitivity without observable toxic side effects in a patient-derived xenograft (PDX) model. Collectively, our findings suggest that TMEM45A may be a therapeutic target for overcoming palbociclib resistance, and exosomal siRNA delivery could be a viable strategy for precision medicine in HR+ breast cancer.https://doi.org/10.1038/s41420-025-02336-9 |
| spellingShingle | Cui Chen Zehong Chen Jinze Zhao Xinyun Wen Hanming Yao Zijin Weng Huiping Xiong Zongheng Zheng Juekun Wu TMEM45A enhances palbociclib resistance and cellular glycolysis by activating AKT/mTOR signaling pathway in HR+ breast cancer Cell Death Discovery |
| title | TMEM45A enhances palbociclib resistance and cellular glycolysis by activating AKT/mTOR signaling pathway in HR+ breast cancer |
| title_full | TMEM45A enhances palbociclib resistance and cellular glycolysis by activating AKT/mTOR signaling pathway in HR+ breast cancer |
| title_fullStr | TMEM45A enhances palbociclib resistance and cellular glycolysis by activating AKT/mTOR signaling pathway in HR+ breast cancer |
| title_full_unstemmed | TMEM45A enhances palbociclib resistance and cellular glycolysis by activating AKT/mTOR signaling pathway in HR+ breast cancer |
| title_short | TMEM45A enhances palbociclib resistance and cellular glycolysis by activating AKT/mTOR signaling pathway in HR+ breast cancer |
| title_sort | tmem45a enhances palbociclib resistance and cellular glycolysis by activating akt mtor signaling pathway in hr breast cancer |
| url | https://doi.org/10.1038/s41420-025-02336-9 |
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