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

Abstract

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.