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. Ivyspring International PublisherResults: 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.

The Use of a Training 3d-Model in the Treatment of a Patient With a Pathological Fracture of the Proximal Part of the Femur (Case From Practice)

“…Онкологічне ураження передміхурової залози є другою за поширеністю причиною злоякісних новоутворень у чоловіків, причому метастази в кістки -джерело захворюваності та смертності в запущених випадках [2,3]. Багаторічний досвід підтверджує, що лімфатичні вузли поблизу первинної пухлини є початковими місцями метастазування, за якими йдуть метастази в кістки [4]. Численні дослідження показали, що люди з кістковими метастазами, спричиненими онкологією передміхурової залози, мають гірший прогноз і знижену якість життя [5,6].…”

Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ

“…An increase in ALDH1A1 in prostate cancer bone metastases was associated with high PLK3 expression. The results demonstrated that ALDH1A1 and PLK3 may serve as biomarkers to predict metastasis and the development of radio-resistance in prostate cancer patients and may represent potential therapeutic targets to eliminate metastatic cells [ 86 ].…”