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

Publication ,  Journal Article
Kim, WK; Buckley, AJ; Lee, D-H; Hiroto, A; Nenninger, CH; Olson, AW; Wang, J; Li, Z; Vikram, R; Adzavon, YM; Yau, T-Y; Bao, Y; Kahn, M ...
Published in: Nat Commun
February 9, 2024

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

February 9, 2024

Volume

15

Issue

1

Start / End Page

1231

Location

England

Related Subject Headings

  • beta Catenin
  • Wnt Signaling Pathway
  • Ribosomal Proteins
  • Receptors, Androgen
  • Prostatic Neoplasms, Castration-Resistant
  • Mice
  • Male
  • Humans
  • Hepatocyte Growth Factor
  • Cell Line, Tumor
 

Citation

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Chicago
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Kim, W. K., Buckley, A. J., Lee, D.-H., Hiroto, A., Nenninger, C. H., Olson, A. W., … Sun, Z. (2024). Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation. Nat Commun, 15(1), 1231. https://doi.org/10.1038/s41467-024-45489-4
Kim, Won Kyung, Alyssa J. Buckley, Dong-Hoon Lee, Alex Hiroto, Christian H. Nenninger, Adam W. Olson, Jinhui Wang, et al. “Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation.Nat Commun 15, no. 1 (February 9, 2024): 1231. https://doi.org/10.1038/s41467-024-45489-4.
Kim WK, Buckley AJ, Lee D-H, Hiroto A, Nenninger CH, Olson AW, et al. Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation. Nat Commun. 2024 Feb 9;15(1):1231.
Kim, Won Kyung, et al. “Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation.Nat Commun, vol. 15, no. 1, Feb. 2024, p. 1231. Pubmed, doi:10.1038/s41467-024-45489-4.
Kim WK, Buckley AJ, Lee D-H, Hiroto A, Nenninger CH, Olson AW, Wang J, Li Z, Vikram R, Adzavon YM, Yau T-Y, Bao Y, Kahn M, Geradts J, Xiao G-Q, Sun Z. Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation. Nat Commun. 2024 Feb 9;15(1):1231.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

February 9, 2024

Volume

15

Issue

1

Start / End Page

1231

Location

England

Related Subject Headings

  • beta Catenin
  • Wnt Signaling Pathway
  • Ribosomal Proteins
  • Receptors, Androgen
  • Prostatic Neoplasms, Castration-Resistant
  • Mice
  • Male
  • Humans
  • Hepatocyte Growth Factor
  • Cell Line, Tumor