The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Cancer stem cells (CSC) are characterized by high self-renewal capacity, tumor-initiating potential, and therapy resistance. Aldehyde dehydrogenase (ALDH)+ cell population serves as an indicator of prostate CSCs with increased therapy resistance, enhanced DNA double-strand break repair, and activated epithelial-mesenchymal transition (EMT) and migration. Numerous ALDH genes contribute to ALDH enzymatic activity; however, only some of them showed clinical relevance. We found that ALDH1A1 and ALDH1A3 genes functionally regulate CSC properties and radiation sensitivity of PCa. We revealed a negative correlation between ALDH1A1 and ALDH1A3 expression in publicly available prostate cancer (PCa) datasets and demonstrated that ALDH1A1 and ALDH1A3 have opposing predictive value for biochemical recurrence-free survival. Our data suggest an association of ALDH1A1 with the metastatic burden, elucidating the role of ALDH genes in the metastatic spread and homing to the bone, which can be, at least partially, attributed to regulating the transforming growth factor beta 1 (TGFB1) and matrix metalloproteinases (MMPs). ALDH genes play a diverse role in PCa development under AR and β-catenin-dependent regulation, with ALDH1A1 becoming dominant in later stages of tumor development when PCa cells gain androgen independence. Taken together, our results indicate that ALDH1A1 and ALDH1A3 modulate PCa radiosensitivity, regulate CSCs phenotype, and spread of PCa cells to the bone, therefore having clinical implication for identifying patients at high risk for progression to metastatic disease. ### Competing Interest Statement The authors have declared no competing interest. * ALDH : aldehyde dehydrogenase AR : androgen receptor BAAA : bodipy-aminoacetaldehyde BAA : bodipy-aminoacetate BM : bone metastatic CSC : cancer stem cell DEAB : diethylaminobenzaldehyde DHT : dihydrotestosterone DMEM : Dulbecco’s Modified Eagles Medium DMSO : dimethyl sulfoxide DoC : duct of Cuvier dpf : days post fertilization DTT : dithiothreitol ECM : extracellular matrix EGF : epidermal growth factor EMT : epithelial-mesenchymal transition Enza : Enzalutamide FBS : fetal bovine serum FFPE : fresh frozen paraffin embedded FGF : fibroblast growth factor FITC : fluorescein isothiocyanate FSC : forward scatter gDNA : genomic DNA i.c. : intracardiac IHC : immunohistochemistry iPSA : initial prostate-specific antigen levels LN : lymph node LM : lung metastatic Luc : luciferase mCRPC : metastatic castration resistant prostate cancer MMP : matrix metalloprotease NSG : NOD scid gamma mouse P : parental PBS : phosphate-buffered saline PCa : prostate cancer PE : plating efficacy PFA : paraformaldehyde PI : propidium iodide PT : primary tumor RPMI : Roswell Park Memorial Institute Medium RR : radioresistant RT : room temperature RT : radiation therapy -RT : sample without added reverse transcriptase enzyme SF : surviving fraction shNA : non-silencing small hairpin RNA shRNA : small hairpin RNA siRNA : small interfering RNA siSCR : scrambled small interfering RNA SPSS : Statistical Package for the Social Sciences SSC : side scatter SUMO : Statistical Utility for Microarray and Omics data software TCGA : The Cancer Genome Atlas TMA : tissue microarray TNM : tumor, nodus и metastasis WF : wide field Zol : zoledronic acid