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Terzic, J.* ; Abu El Maaty, M.A. ; Lutzing, R.* ; Vincent, A.* ; El Bizri, R.* ; Jung, M.* ; Keime, C.* ; Metzger, D.*

Hypoxia-inducible factor 1A inhibition overcomes castration resistance of prostate tumors.

EMBO Mol. Med. 15:e17209 (2023)

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Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone-independent state termed castration-resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten^(i)pe-/- mice, generated by luminal epithelial cell-specific deletion of the tumor suppressor PTEN after puberty, is castration-resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia-inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of Pten^(i)pe-/- mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten-deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Hif1a ; Pten ; Castration-resistant Prostate Cancer ; Genetically-engineered Mice ; Single-cell Rna Sequencing; Cancer; Pten; Plasticity; Px-478; Cells

ISSN (print) / ISBN 1757-4676

e-ISSN 1757-4684

Journal EMBO Molecular Medicine

Quellenangaben Volume: 15, Issue: 6, Article Number: e17209

Publisher Wiley

Publishing Place Chichester

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Cancer (IDC)

Grants Centre National de la Recherche Scientifique (CNRS)
Institut National de la Sante et de la Recherche Medicale (INSERM)
Universite de Strasbourg
Interdisciplinary Thematic Institute IMCBio, as part of the ITI 2021-2028 program of the University of Strasbourg
CNRS
Inserm
IdEx Unistra
SFRI-STRAT'US project
EUR IMCBio
France Genomique consortium
ITMO Cancer within the funds of the Cancer Plan 2014-2019
French National Cancer Institute
INCa-PLBIO
Fondation ARC pour la Recherche sur le Cancer
Agence Nationale de la Recherche
ITMO Cancer Aviesan/Inserm/Cancer 2020 through the "Formation a la recherche fondamentale et translationnelle en cancerologie" program
Al Bizri Foundation
Agence Nationale de la Recherche (ANR)
Fondation pour la Recherche Medicale grant