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ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription

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ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription. / Gorodetska, Ielizaveta; Offermann, Anne; Püschel, Jakob; Lukiyanchuk, Vasyl; Gaete, Diana; Kurzyukova, Anastasia; Freytag, Vera; Haider, Marie-Therese; Fjeldbo, Christina S; Di Gaetano, Simona; Schwarz, Franziska Maria; Patil, Shivaprasad; Borkowetz, Angelika; Erb, Holger H H; Baniahmad, Aria; Mircetic, Jovan; Lyng, Heidi; Löck, Steffen; Linge, Annett; Lange, Tobias; Knopf, Franziska; Wielockx, Ben; Krause, Mechthild; Perner, Sven; Dubrovska, Anna.

in: THERANOSTICS, Jahrgang 14, Nr. 2, 2024, S. 714-737.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Gorodetska, I, Offermann, A, Püschel, J, Lukiyanchuk, V, Gaete, D, Kurzyukova, A, Freytag, V, Haider, M-T, Fjeldbo, CS, Di Gaetano, S, Schwarz, FM, Patil, S, Borkowetz, A, Erb, HHH, Baniahmad, A, Mircetic, J, Lyng, H, Löck, S, Linge, A, Lange, T, Knopf, F, Wielockx, B, Krause, M, Perner, S & Dubrovska, A 2024, 'ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription', THERANOSTICS, Jg. 14, Nr. 2, S. 714-737. https://doi.org/10.7150/thno.88057

APA

Gorodetska, I., Offermann, A., Püschel, J., Lukiyanchuk, V., Gaete, D., Kurzyukova, A., Freytag, V., Haider, M-T., Fjeldbo, C. S., Di Gaetano, S., Schwarz, F. M., Patil, S., Borkowetz, A., Erb, H. H. H., Baniahmad, A., Mircetic, J., Lyng, H., Löck, S., Linge, A., ... Dubrovska, A. (2024). ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription. THERANOSTICS, 14(2), 714-737. https://doi.org/10.7150/thno.88057

Vancouver

Gorodetska I, Offermann A, Püschel J, Lukiyanchuk V, Gaete D, Kurzyukova A et al. ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription. THERANOSTICS. 2024;14(2):714-737. https://doi.org/10.7150/thno.88057

Bibtex

@article{6ac268d3e165451c99107a809861c2c7,
title = "ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription",
abstract = "Rationale: Current therapies for metastatic osseous disease frequently fail to provide a durable treatment response. To date, there are only limited therapeutic options for metastatic prostate cancer, the mechanisms that drive the survival of metastasis-initiating cells are poorly characterized, and reliable prognostic markers are missing. A high aldehyde dehydrogenase (ALDH) activity has been long considered a marker of cancer stem cells (CSC). Our study characterized a differential role of ALDH1A1 and ALDH1A3 genes as regulators of prostate cancer progression and metastatic growth. Methods: By genetic silencing of ALDH1A1 and ALDH1A3 in vitro, in xenografted zebrafish and murine models, and by comparative immunohistochemical analyses of benign, primary tumor, and metastatic specimens from patients with prostate cancer, we demonstrated that ALDH1A1 and ALDH1A3 maintain the CSC phenotype and radioresistance and regulate bone metastasis-initiating cells. We have validated ALDH1A1 and ALDH1A3 as potential biomarkers of clinical outcomes in the independent cohorts of patients with PCa. Furthermore, by RNAseq, chromatin immunoprecipitation (ChIP), and biostatistics analyses, we suggested the molecular mechanisms explaining the role of ALDH1A1 in PCa progression. Results: We found that aldehyde dehydrogenase protein ALDH1A1 positively regulates tumor cell survival in circulation, extravasation, and metastatic dissemination, whereas ALDH1A3 plays the opposite role. ALDH1A1 and ALDH1A3 are differentially expressed in metastatic tumors of patients with prostate cancer, and their expression levels oppositely correlate with clinical outcomes. Prostate cancer progression is associated with the increasing interplay of ALDH1A1 with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs. Polo-like kinase 3 (PLK3) was identified as a transcriptional target oppositely regulated by ALDH1A1 and ALDH1A3 genes in RAR and AR-dependent manner. PLK3 contributes to the control of prostate cancer cell proliferation, migration, DNA repair, and radioresistance. ALDH1A1 gain in prostate cancer bone metastases is associated with high PLK3 expression. Conclusion: This report provides the first evidence that ALDH1A1 and PLK3 could serve as biomarkers to predict metastatic dissemination and radiotherapy resistance in patients with prostate cancer and could be potential therapeutic targets to eliminate metastasis-initiating and radioresistant tumor cell populations.",
keywords = "Male, Humans, Animals, Mice, Receptors, Androgen, Zebrafish/metabolism, Cell Line, Tumor, Aldehyde Dehydrogenase/genetics, Prostatic Neoplasms/genetics, Biomarkers, Aldehyde Dehydrogenase 1 Family, Retinal Dehydrogenase",
author = "Ielizaveta Gorodetska and Anne Offermann and Jakob P{\"u}schel and Vasyl Lukiyanchuk and Diana Gaete and Anastasia Kurzyukova and Vera Freytag and Marie-Therese Haider and Fjeldbo, {Christina S} and {Di Gaetano}, Simona and Schwarz, {Franziska Maria} and Shivaprasad Patil and Angelika Borkowetz and Erb, {Holger H H} and Aria Baniahmad and Jovan Mircetic and Heidi Lyng and Steffen L{\"o}ck and Annett Linge and Tobias Lange and Franziska Knopf and Ben Wielockx and Mechthild Krause and Sven Perner and Anna Dubrovska",
note = "{\textcopyright} The author(s).",
year = "2024",
doi = "10.7150/thno.88057",
language = "English",
volume = "14",
pages = "714--737",
journal = "THERANOSTICS",
issn = "1838-7640",
publisher = "Ivyspring International Publisher",
number = "2",

}

RIS

TY - JOUR

T1 - ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription

AU - Gorodetska, Ielizaveta

AU - Offermann, Anne

AU - Püschel, Jakob

AU - Lukiyanchuk, Vasyl

AU - Gaete, Diana

AU - Kurzyukova, Anastasia

AU - Freytag, Vera

AU - Haider, Marie-Therese

AU - Fjeldbo, Christina S

AU - Di Gaetano, Simona

AU - Schwarz, Franziska Maria

AU - Patil, Shivaprasad

AU - Borkowetz, Angelika

AU - Erb, Holger H H

AU - Baniahmad, Aria

AU - Mircetic, Jovan

AU - Lyng, Heidi

AU - Löck, Steffen

AU - Linge, Annett

AU - Lange, Tobias

AU - Knopf, Franziska

AU - Wielockx, Ben

AU - Krause, Mechthild

AU - Perner, Sven

AU - Dubrovska, Anna

N1 - © The author(s).

PY - 2024

Y1 - 2024

N2 - Rationale: Current therapies for metastatic osseous disease frequently fail to provide a durable treatment response. To date, there are only limited therapeutic options for metastatic prostate cancer, the mechanisms that drive the survival of metastasis-initiating cells are poorly characterized, and reliable prognostic markers are missing. A high aldehyde dehydrogenase (ALDH) activity has been long considered a marker of cancer stem cells (CSC). Our study characterized a differential role of ALDH1A1 and ALDH1A3 genes as regulators of prostate cancer progression and metastatic growth. Methods: By genetic silencing of ALDH1A1 and ALDH1A3 in vitro, in xenografted zebrafish and murine models, and by comparative immunohistochemical analyses of benign, primary tumor, and metastatic specimens from patients with prostate cancer, we demonstrated that ALDH1A1 and ALDH1A3 maintain the CSC phenotype and radioresistance and regulate bone metastasis-initiating cells. We have validated ALDH1A1 and ALDH1A3 as potential biomarkers of clinical outcomes in the independent cohorts of patients with PCa. Furthermore, by RNAseq, chromatin immunoprecipitation (ChIP), and biostatistics analyses, we suggested the molecular mechanisms explaining the role of ALDH1A1 in PCa progression. Results: We found that aldehyde dehydrogenase protein ALDH1A1 positively regulates tumor cell survival in circulation, extravasation, and metastatic dissemination, whereas ALDH1A3 plays the opposite role. ALDH1A1 and ALDH1A3 are differentially expressed in metastatic tumors of patients with prostate cancer, and their expression levels oppositely correlate with clinical outcomes. Prostate cancer progression is associated with the increasing interplay of ALDH1A1 with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs. Polo-like kinase 3 (PLK3) was identified as a transcriptional target oppositely regulated by ALDH1A1 and ALDH1A3 genes in RAR and AR-dependent manner. PLK3 contributes to the control of prostate cancer cell proliferation, migration, DNA repair, and radioresistance. ALDH1A1 gain in prostate cancer bone metastases is associated with high PLK3 expression. Conclusion: This report provides the first evidence that ALDH1A1 and PLK3 could serve as biomarkers to predict metastatic dissemination and radiotherapy resistance in patients with prostate cancer and could be potential therapeutic targets to eliminate metastasis-initiating and radioresistant tumor cell populations.

AB - Rationale: Current therapies for metastatic osseous disease frequently fail to provide a durable treatment response. To date, there are only limited therapeutic options for metastatic prostate cancer, the mechanisms that drive the survival of metastasis-initiating cells are poorly characterized, and reliable prognostic markers are missing. A high aldehyde dehydrogenase (ALDH) activity has been long considered a marker of cancer stem cells (CSC). Our study characterized a differential role of ALDH1A1 and ALDH1A3 genes as regulators of prostate cancer progression and metastatic growth. Methods: By genetic silencing of ALDH1A1 and ALDH1A3 in vitro, in xenografted zebrafish and murine models, and by comparative immunohistochemical analyses of benign, primary tumor, and metastatic specimens from patients with prostate cancer, we demonstrated that ALDH1A1 and ALDH1A3 maintain the CSC phenotype and radioresistance and regulate bone metastasis-initiating cells. We have validated ALDH1A1 and ALDH1A3 as potential biomarkers of clinical outcomes in the independent cohorts of patients with PCa. Furthermore, by RNAseq, chromatin immunoprecipitation (ChIP), and biostatistics analyses, we suggested the molecular mechanisms explaining the role of ALDH1A1 in PCa progression. Results: We found that aldehyde dehydrogenase protein ALDH1A1 positively regulates tumor cell survival in circulation, extravasation, and metastatic dissemination, whereas ALDH1A3 plays the opposite role. ALDH1A1 and ALDH1A3 are differentially expressed in metastatic tumors of patients with prostate cancer, and their expression levels oppositely correlate with clinical outcomes. Prostate cancer progression is associated with the increasing interplay of ALDH1A1 with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs. Polo-like kinase 3 (PLK3) was identified as a transcriptional target oppositely regulated by ALDH1A1 and ALDH1A3 genes in RAR and AR-dependent manner. PLK3 contributes to the control of prostate cancer cell proliferation, migration, DNA repair, and radioresistance. ALDH1A1 gain in prostate cancer bone metastases is associated with high PLK3 expression. Conclusion: This report provides the first evidence that ALDH1A1 and PLK3 could serve as biomarkers to predict metastatic dissemination and radiotherapy resistance in patients with prostate cancer and could be potential therapeutic targets to eliminate metastasis-initiating and radioresistant tumor cell populations.

KW - Male

KW - Humans

KW - Animals

KW - Mice

KW - Receptors, Androgen

KW - Zebrafish/metabolism

KW - Cell Line, Tumor

KW - Aldehyde Dehydrogenase/genetics

KW - Prostatic Neoplasms/genetics

KW - Biomarkers

KW - Aldehyde Dehydrogenase 1 Family

KW - Retinal Dehydrogenase

U2 - 10.7150/thno.88057

DO - 10.7150/thno.88057

M3 - SCORING: Journal article

C2 - 38169509

VL - 14

SP - 714

EP - 737

JO - THERANOSTICS

JF - THERANOSTICS

SN - 1838-7640

IS - 2

ER -