Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation

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 and Zijie Sun ()
Additional contact information
Won Kyung Kim: Cancer Center and Beckman Research Institute, City of Hope
Alyssa J. Buckley: Cancer Center and Beckman Research Institute, City of Hope
Dong-Hoon Lee: Cancer Center and Beckman Research Institute, City of Hope
Alex Hiroto: Cancer Center and Beckman Research Institute, City of Hope
Christian H. Nenninger: Cancer Center and Beckman Research Institute, City of Hope
Adam W. Olson: Cancer Center and Beckman Research Institute, City of Hope
Jinhui Wang: Cancer Center and Beckman Research Institute, City of Hope
Zhuo Li: Cancer Center and Beckman Research Institute, City of Hope
Rajeev Vikram: Cancer Center and Beckman Research Institute, City of Hope
Yao Mawulikplimi Adzavon: Cancer Center and Beckman Research Institute, City of Hope
Tak-yu Yau: Cancer Center and Beckman Research Institute, City of Hope
Yigang Bao: Cancer Center and Beckman Research Institute, City of Hope
Michael Kahn: Cancer Center and Beckman Research Institute, City of Hope
Joseph Geradts: East Carolina University
Guang-Qian Xiao: University of Southern California
Zijie Sun: Cancer Center and Beckman Research Institute, City of Hope

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45489-4

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