Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis
Ferroptosis, an iron-dependent lipid peroxidation-driven programmed cell death, is closely related to cancer therapy. The development of druggable ferroptosis inducers and their rational application in cancer therapy are critical. Here, we identified Tubastatin A, an HDAC6 inhibitor as a novel drugg...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-06-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723000782 |
| _version_ | 1827950724503306240 |
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| author | Shan Liu Hai-Liang Zhang Jing Li Zhi-Peng Ye Tian Du Li-Chao Li Yi-Qing Guo Dong Yang Zhi-Ling Li Jiang-Hua Cao Bing-Xin Hu Yu-Hong Chen Gong-Kan Feng Zhi-Ming Li Rong Deng Jia-Jia Huang Xiao-Feng Zhu |
| author_facet | Shan Liu Hai-Liang Zhang Jing Li Zhi-Peng Ye Tian Du Li-Chao Li Yi-Qing Guo Dong Yang Zhi-Ling Li Jiang-Hua Cao Bing-Xin Hu Yu-Hong Chen Gong-Kan Feng Zhi-Ming Li Rong Deng Jia-Jia Huang Xiao-Feng Zhu |
| author_sort | Shan Liu |
| collection | DOAJ |
| description | Ferroptosis, an iron-dependent lipid peroxidation-driven programmed cell death, is closely related to cancer therapy. The development of druggable ferroptosis inducers and their rational application in cancer therapy are critical. Here, we identified Tubastatin A, an HDAC6 inhibitor as a novel druggable ferroptosis inducer through large-scale drug screening. Tubastatin A directly bonded to GPX4 and inhibited GPX4 enzymatic activity through biotin-linked Tubastatin A putdown and LC/MS analysis, which is independent of its inhibition of HDAC6. In addition, our results showed that radiotherapy not only activated Nrf2-mediated GPX4 transcription but also inhibited lysosome-mediated GPX4 degradation, subsequently inducing ferroptosis tolerance and radioresistance in cancer cells. Tubastatin A overcame ferroptosis resistance and radioresistance of cancer cells by inhibiting GPX4 enzymatic activity. More importantly, Tubastatin A has excellent bioavailability, as demonstrated by its ability to significantly promote radiotherapy-induced lipid peroxidation and tumour suppression in a mouse xenograft model. Our findings identify a novel druggable ferroptosis inducer, Tubastatin A, which enhances radiotherapy-mediated antitumor effects. This work provides a compelling rationale for the clinical evaluation of Tubastatin A, especially in combination with radiotherapy. |
| first_indexed | 2024-04-09T13:31:11Z |
| format | Article |
| id | doaj.art-cc455e40662a47a2a8b83d1c0b4d5347 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-09T13:31:11Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-cc455e40662a47a2a8b83d1c0b4d53472023-05-10T04:19:03ZengElsevierRedox Biology2213-23172023-06-0162102677Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosisShan Liu0Hai-Liang Zhang1Jing Li2Zhi-Peng Ye3Tian Du4Li-Chao Li5Yi-Qing Guo6Dong Yang7Zhi-Ling Li8Jiang-Hua Cao9Bing-Xin Hu10Yu-Hong Chen11Gong-Kan Feng12Zhi-Ming Li13Rong Deng14Jia-Jia Huang15Xiao-Feng Zhu16State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China; Corresponding author. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Corresponding author. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China; Corresponding author. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China..Ferroptosis, an iron-dependent lipid peroxidation-driven programmed cell death, is closely related to cancer therapy. The development of druggable ferroptosis inducers and their rational application in cancer therapy are critical. Here, we identified Tubastatin A, an HDAC6 inhibitor as a novel druggable ferroptosis inducer through large-scale drug screening. Tubastatin A directly bonded to GPX4 and inhibited GPX4 enzymatic activity through biotin-linked Tubastatin A putdown and LC/MS analysis, which is independent of its inhibition of HDAC6. In addition, our results showed that radiotherapy not only activated Nrf2-mediated GPX4 transcription but also inhibited lysosome-mediated GPX4 degradation, subsequently inducing ferroptosis tolerance and radioresistance in cancer cells. Tubastatin A overcame ferroptosis resistance and radioresistance of cancer cells by inhibiting GPX4 enzymatic activity. More importantly, Tubastatin A has excellent bioavailability, as demonstrated by its ability to significantly promote radiotherapy-induced lipid peroxidation and tumour suppression in a mouse xenograft model. Our findings identify a novel druggable ferroptosis inducer, Tubastatin A, which enhances radiotherapy-mediated antitumor effects. This work provides a compelling rationale for the clinical evaluation of Tubastatin A, especially in combination with radiotherapy.http://www.sciencedirect.com/science/article/pii/S2213231723000782 |
| spellingShingle | Shan Liu Hai-Liang Zhang Jing Li Zhi-Peng Ye Tian Du Li-Chao Li Yi-Qing Guo Dong Yang Zhi-Ling Li Jiang-Hua Cao Bing-Xin Hu Yu-Hong Chen Gong-Kan Feng Zhi-Ming Li Rong Deng Jia-Jia Huang Xiao-Feng Zhu Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis Redox Biology |
| title | Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis |
| title_full | Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis |
| title_fullStr | Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis |
| title_full_unstemmed | Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis |
| title_short | Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis |
| title_sort | tubastatin a potently inhibits gpx4 activity to potentiate cancer radiotherapy through boosting ferroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723000782 |
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