Role of Retinoic Acid-Metabolizing Cytochrome P450s, CYP26, in Inflammation and Cancer

Abstract

Vitamin A (retinol) and its active metabolite, all-trans-retinoic acid (atRA), play critical roles in regulating the differentiation, growth and migration of immune cells. Similarly, as critical signaling molecules in the regulation of the cell cycle, retinoids are important in cancers. Concentrations of atRA are tightly regulated in tissues, predominantly by the availability of retinol, synthesis of atRA by ALDH1A enzymes and metabolism and clearance of atRA by CYP26 enzymes. The ALDH1A and CYP26 enzymes are expressed in several cell types in the immune system and in cancer cells. In the immune system the ALDH1A and CYP26 enzymes appear to modulate RA concentrations. Consequently, alterations in the activity of ALDH1A and CYP26 enzymes are expected to change disease outcomes in inflammation. There is increasing evidence from various disease models of intestinal and skin inflammation that treatment with atRA has a positive effect on disease markers. However, whether aberrant atRA concentrations or atRA synthesis and metabolism play a role in inflammatory disease development and progression is not well understood. In cancers, especially in acute promyelocytic leukemia and neuroblastoma, increasing intracellular concentrations of atRA appears to provide clinical benefit. Inhibition of the CYP26 enzymes to increase atRA concentrations and combat therapy resistance has been pursued as a drug target in these cancers. This chapter covers the current knowledge of how atRA and retinol regulate the immune system and inflammation, how retinol and atRA metabolism is altered in inflammation and cancer and what roles atRA metabolizing enzymes have in immune responses and cancers.

All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-αand Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer

“…Several hematopoietic and nonhematopoietic lineages within the gastrointestinal tract, including macrophages, dendritic cells, and lymphocytes T share the capacity to synthesize retinoic acid [78, 79]. A number of studies demonstrated that AtRA has an important modulating role in innate immunity, with the most recent reports showing that RA has a central function in the differentiation of dendritic cells (DCs), the key APCs for activating naive T cells [80, 81].…”

Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: Effects on retinoid metabolism, function and related diseases

“…Emerging data about BP, for example, recurrently provide new insight that should direct therapy, or at least aid diagnosis, and new retinoids are consistently evaluated to improve therapeutic utility, as well use as a component of combination therapy. Alternative approaches to increasing intracellular atRA by inhibiting catabolism also undergo consideration to treat retinoid-related diseases (Stevison et al, 2015). …”

Generating retinoic acid gradients by local degradation during craniofacial development: One cell's cue is another cell's poison

“…However, given that RA is degraded in several local domains in tissues, the systemic concentration of RA in human plasma is not an accurate indicator of overall RA homeostasis and metabolism (Stevison, Jing, Tripathy, & Isoherranen, 2015). Cyp26 enzymes need a membrane environment for activity due to their requirement for P450 reductase, present in the ER membrane (Lutz et al, 2009;Stevison et al, 2015). Hence their activity is often assessed using recombinant proteins in preparations of microsomal fractions isolated from tissues and cell lines.…”