The Expanding Role of Cancer Stem Cell Marker ALDH1A3 in Cancer and Beyond

SIMPLE SUMMARY: Aldehyde dehydrogenase 1A3 (ALDH1A3) is the primary cause of the high ALDH activity associated with cancer stem cell (CSC) populations in multiple cancers and its expression promotes cancer progression. Here in, we review the role of ALDH1A3 in normal physiology, cancer, and other diseases. Finally, we discuss the emerging potential of targeting ALDH1A3 with non-specific and specific inhibitors. ABSTRACT: Aldehyde dehydrogenase 1A3 (ALDH1A3) is one of 19 ALDH enzymes expressed in humans, and it is critical in the production of hormone receptor ligand retinoic acid (RA). We review the role of ALDH1A3 in normal physiology, its identification as a cancer stem cell marker, and its modes of action in cancer and other diseases. ALDH1A3 is often over-expressed in cancer and promotes tumor growth, metastasis, and chemoresistance by altering gene expression, cell signaling pathways, and glycometabolism. The increased levels of ALDH1A3 in cancer occur due to genetic amplification, epigenetic modifications, post-transcriptional regulation, and post-translational modification. Finally, we review the potential of targeting ALDH1A3, with both general ALDH inhibitors and small molecules specifically designed to inhibit ALDH1A3 activity.