Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α

Retinoic acid receptor-related orphan receptor-alpha (ROR alpha) is a member of the orphan nuclear receptor family and functions as a transcriptional activator in response to circadian changes. Circadian rhythms are complex cellular mechanisms regulating diverse metabolic, inflammatory, and tumorigenic gene expression pathways that govern cyclic cellular physiology. Disruption of circadian regulators, including ROR alpha, plays a critical role in tumorigenesis and facilitates the development of inflammatory hallmarks. Although ROR alpha contributes to overall fitness among anticancer, anti-inflammatory, lipid homeostasis, and circadian clock mechanisms, the molecular mechanisms underlying the mode of transcriptional regulation by ROR alpha remain unclear. Nonetheless, ROR alpha has important implications for pharmacological prevention of cancer, inflammation, and metabolic diseases, and understanding context-dependent ROR alpha regulation will provide an innovative approach for unraveling the functional link between cancer metabolism and rhythm changes. Receptor proteins: adopting an orphan to understand and treat disease The protein known as retinoic acid receptor-related orphan receptor alpha (ROR alpha) activates specific genes in response to the daily cellular changes associated with circadian rhythms, and disruption of its activity is associated with cancer, inflammation and metabolic diseases. Proteins like ROR alpha are called orphan receptors because the molecules that bind to them to initiate their activities are unknown or unconfirmed. Ji Min Lee at Kangwon National University, Chuncheon, South Korea and colleagues review current understanding of the activities of ROR alpha, including the molecular mechanisms underlying its likely involvement in various diseases. They highlight the possible significance of manipulating ROR alpha activity as a route towards new treatments for several diseases including cancer. Pharmaceutical companies are exploring the therapeutic possibilities of molecules that can bind to and activate ROR alpha, especially natural products.