AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer
Abstract Cancer cells can be induced to dormancy initially by specific cancer therapies, but can be reactivated for subsequent relapse as therapy-resistant cancer cells. Although the treatment-induced dormancy-to-reactivation switch is an important process in tumour spread and recurrence, little is...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-08-01
|
| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-025-00817-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849333759850053632 |
|---|---|
| author | Sangsang Li Yifan Zhang Maoxing Luo Weiwei Zhou Yitong Chen Dinglan Wu Qiang Wei Yan Chang Hailiang Hu |
| author_facet | Sangsang Li Yifan Zhang Maoxing Luo Weiwei Zhou Yitong Chen Dinglan Wu Qiang Wei Yan Chang Hailiang Hu |
| author_sort | Sangsang Li |
| collection | DOAJ |
| description | Abstract Cancer cells can be induced to dormancy initially by specific cancer therapies, but can be reactivated for subsequent relapse as therapy-resistant cancer cells. Although the treatment-induced dormancy-to-reactivation switch is an important process in tumour spread and recurrence, little is known about the underlying molecular mechanisms, particularly the metabolic underpinnings. In this study, we demonstrated that the tryptophan catabolism-related tryptophan 2,3-dioxygenase (TDO2) -kynurenine (Kyn) -aryl hydrocarbon receptor (AhR) signalling axis was responsible for both sustaining the survival of dormant prostate cancer cells induced by androgen deprivation therapy (ADT) and promoting the reactivation of dormant cells and their recurrent outgrowth, which facilitated the development of therapeutic resistance by allowing the dormancy-to-reactivation switch. Mechanistically, we found that ADT upregulated the expression of TDO2 to produce Kyn, which activated AhR and maintained the survival of ADT-induced dormant cells. Interestingly, the switch of transcription factors from the androgen receptor (AR) to the glucocorticoid receptor (GR) modulated the persistent expression of TDO2 and promoted the reactivation of dormant cells through the same TDO2-Kyn-AhR signalling axis. Additionally, tumour recurrence following ADT was delayed by pharmacological suppression of TDO2-Kyn-AhR signalling with a TDO2 inhibitor or an AhR inhibitor. In summary, we describe a signalling circuit mediated by tryptophan metabolism for regulating tumour cell dormancy and recurrence and propose TDO2 as a new target for the treatment of androgen-sensitive prostate cancer patients in combination with ADT. |
| format | Article |
| id | doaj-art-24eaf36d405a4ba48d36c3cc18723ca5 |
| institution | Kabale University |
| issn | 2056-5968 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj-art-24eaf36d405a4ba48d36c3cc18723ca52025-08-20T03:45:45ZengNature Publishing GroupCell Discovery2056-59682025-08-0111111610.1038/s41421-025-00817-wAR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancerSangsang Li0Yifan Zhang1Maoxing Luo2Weiwei Zhou3Yitong Chen4Dinglan Wu5Qiang Wei6Yan Chang7Hailiang Hu8Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and TechnologyDepartment of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and TechnologyDepartment of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and TechnologyDepartment of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and TechnologyDepartment of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and TechnologyShenzhen Key Laboratory of Viral Oncology, Clinical Innovation and Research Center (CIRC), Shenzhen Hospital of Southern Medical UniversityDepartment of Urology, Nanfang Hospital, Southern Medical UniversityInstitute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of EducationDepartment of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and TechnologyAbstract Cancer cells can be induced to dormancy initially by specific cancer therapies, but can be reactivated for subsequent relapse as therapy-resistant cancer cells. Although the treatment-induced dormancy-to-reactivation switch is an important process in tumour spread and recurrence, little is known about the underlying molecular mechanisms, particularly the metabolic underpinnings. In this study, we demonstrated that the tryptophan catabolism-related tryptophan 2,3-dioxygenase (TDO2) -kynurenine (Kyn) -aryl hydrocarbon receptor (AhR) signalling axis was responsible for both sustaining the survival of dormant prostate cancer cells induced by androgen deprivation therapy (ADT) and promoting the reactivation of dormant cells and their recurrent outgrowth, which facilitated the development of therapeutic resistance by allowing the dormancy-to-reactivation switch. Mechanistically, we found that ADT upregulated the expression of TDO2 to produce Kyn, which activated AhR and maintained the survival of ADT-induced dormant cells. Interestingly, the switch of transcription factors from the androgen receptor (AR) to the glucocorticoid receptor (GR) modulated the persistent expression of TDO2 and promoted the reactivation of dormant cells through the same TDO2-Kyn-AhR signalling axis. Additionally, tumour recurrence following ADT was delayed by pharmacological suppression of TDO2-Kyn-AhR signalling with a TDO2 inhibitor or an AhR inhibitor. In summary, we describe a signalling circuit mediated by tryptophan metabolism for regulating tumour cell dormancy and recurrence and propose TDO2 as a new target for the treatment of androgen-sensitive prostate cancer patients in combination with ADT.https://doi.org/10.1038/s41421-025-00817-w |
| spellingShingle | Sangsang Li Yifan Zhang Maoxing Luo Weiwei Zhou Yitong Chen Dinglan Wu Qiang Wei Yan Chang Hailiang Hu AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer Cell Discovery |
| title | AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer |
| title_full | AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer |
| title_fullStr | AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer |
| title_full_unstemmed | AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer |
| title_short | AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer |
| title_sort | ar to gr switch modulates differential tdo2 kyn ahr signalling to promote the survival and recurrence of treatment induced dormant cells in prostate cancer |
| url | https://doi.org/10.1038/s41421-025-00817-w |
| work_keys_str_mv | AT sangsangli artogrswitchmodulatesdifferentialtdo2kynahrsignallingtopromotethesurvivalandrecurrenceoftreatmentinduceddormantcellsinprostatecancer AT yifanzhang artogrswitchmodulatesdifferentialtdo2kynahrsignallingtopromotethesurvivalandrecurrenceoftreatmentinduceddormantcellsinprostatecancer AT maoxingluo artogrswitchmodulatesdifferentialtdo2kynahrsignallingtopromotethesurvivalandrecurrenceoftreatmentinduceddormantcellsinprostatecancer AT weiweizhou artogrswitchmodulatesdifferentialtdo2kynahrsignallingtopromotethesurvivalandrecurrenceoftreatmentinduceddormantcellsinprostatecancer AT yitongchen artogrswitchmodulatesdifferentialtdo2kynahrsignallingtopromotethesurvivalandrecurrenceoftreatmentinduceddormantcellsinprostatecancer AT dinglanwu artogrswitchmodulatesdifferentialtdo2kynahrsignallingtopromotethesurvivalandrecurrenceoftreatmentinduceddormantcellsinprostatecancer AT qiangwei artogrswitchmodulatesdifferentialtdo2kynahrsignallingtopromotethesurvivalandrecurrenceoftreatmentinduceddormantcellsinprostatecancer AT yanchang artogrswitchmodulatesdifferentialtdo2kynahrsignallingtopromotethesurvivalandrecurrenceoftreatmentinduceddormantcellsinprostatecancer AT hailianghu artogrswitchmodulatesdifferentialtdo2kynahrsignallingtopromotethesurvivalandrecurrenceoftreatmentinduceddormantcellsinprostatecancer |