Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation
Abstract Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45489-4 |
| _version_ | 1797274040866439168 |
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| author | Won Kyung Kim Alyssa J. Buckley Dong-Hoon Lee Alex Hiroto Christian H. Nenninger Adam W. Olson Jinhui Wang Zhuo Li Rajeev Vikram Yao Mawulikplimi Adzavon Tak-yu Yau Yigang Bao Michael Kahn Joseph Geradts Guang-Qian Xiao Zijie Sun |
| author_facet | Won Kyung Kim Alyssa J. Buckley Dong-Hoon Lee Alex Hiroto Christian H. Nenninger Adam W. Olson Jinhui Wang Zhuo Li Rajeev Vikram Yao Mawulikplimi Adzavon Tak-yu Yau Yigang Bao Michael Kahn Joseph Geradts Guang-Qian Xiao Zijie Sun |
| author_sort | Won Kyung Kim |
| collection | DOAJ |
| description | Abstract Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/β-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/β-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets. |
| first_indexed | 2024-03-07T14:52:42Z |
| format | Article |
| id | doaj.art-8c69e3a71f664fe7bd43113f313a328f |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:42Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8c69e3a71f664fe7bd43113f313a328f2024-03-05T19:37:10ZengNature PortfolioNature Communications2041-17232024-02-0115111810.1038/s41467-024-45489-4Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activationWon Kyung Kim0Alyssa J. Buckley1Dong-Hoon Lee2Alex Hiroto3Christian H. Nenninger4Adam W. Olson5Jinhui Wang6Zhuo Li7Rajeev Vikram8Yao Mawulikplimi Adzavon9Tak-yu Yau10Yigang Bao11Michael Kahn12Joseph Geradts13Guang-Qian Xiao14Zijie Sun15Department of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeIntegrative Genomics Core, Cancer Center and Beckman Research Institute, City of HopeElectronic Microscopy Core, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeDepartment of Pathology and Laboratory Medicine, Brody School of Medicine, East Carolina UniversityDepartment of Pathology, Keck School of Medicine, University of Southern CaliforniaDepartment of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of HopeAbstract Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/β-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/β-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets.https://doi.org/10.1038/s41467-024-45489-4 |
| spellingShingle | Won Kyung Kim Alyssa J. Buckley Dong-Hoon Lee Alex Hiroto Christian H. Nenninger Adam W. Olson Jinhui Wang Zhuo Li Rajeev Vikram Yao Mawulikplimi Adzavon Tak-yu Yau Yigang Bao Michael Kahn Joseph Geradts Guang-Qian Xiao Zijie Sun Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation Nature Communications |
| title | Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation |
| title_full | Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation |
| title_fullStr | Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation |
| title_full_unstemmed | Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation |
| title_short | Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation |
| title_sort | androgen deprivation induces double null prostate cancer via aberrant nuclear export and ribosomal biogenesis through hgf and wnt activation |
| url | https://doi.org/10.1038/s41467-024-45489-4 |
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