Vitamin A‐mediated inhibition of cell cycle progression proteins and cell growth requires protein‐bound retinol in a prostate cancer cell line

Abstract

Stimulated by retinoic acid homolog 6 (STRA6) is a transmembrane receptor specific for retinol‐binding protein 4 (RBP4) that mediates uptake of retinol bound to RBP4 (HoloRBP4). Retinoic acid derivatives of retinol have well‐documented anti‐proliferative actions that are mediated by retinoic acid and retinoid X receptors (RAR and RXR, respectively). Thus, it has long been assumed that the effects of circulating retinol on the regulation of apoptosis are dependent on cellular uptake of retinol and activation to retinoic acid. An additional role of STRA6 has recently been identified in vivo and in cultured hepatocytes and renal proximal tubule cells. Upon binding to holoRBP4, STRA6 has been shown to activate a cascade that led to STAT5‐mediated gene regulation. We have detected and induced STRA6 with all‐trans‐retinoic acid (RA) in PC‐3 prostate cancer cells. In this study, we found that PC‐3 cells were growth inhibited following treatment with holoRBP4 whereas 1 μmol/L RA treatment had no effect. Furthermore, we observed that holoRBP4 treatment reduced mRNA and protein abundance of cell cycle progression proteins (CD1, CDK2, and CDK4), which have been identified as a downstream target of STAT5. Collectively, these results indicate that anti‐proliferative actions of retinol may be produced via a signal transduction mechanism, which appear to occur independently of RA‐mediated gene regulation.Grant Funding Source: National Institutes of Health