Retinoic Acid Receptor ß: A Potential Therapeutic Target in Retinoic Acid Treatment of Endometrial Cancer.

OBJECTIVE: Several studies have reported that retinoic acid (RA) might be used to treat malignancies. The effects of RA are mediated by the RA receptor (RAR), and RARα/RARß especially acts as a tumor suppressor. However, little is known about its role in human endometrial cancer. MATERIALS AND METHODS: In this study, we examined the effects of all-trans RA (ATRA) on progression of human endometrial cancer cell line, RL95-2 and Hec1A. We then examined the expression of RARα and RARß in 50 endometrial cancer tissues by using immunohistochemistry. RESULTS: We found inhibitory effects of ATRA on cell proliferation, apoptosis, and migration in RL95-2 cells, but not in Hec1A cells. RARα or RARß knockdown individually could not cancel out the inhibition of cell proliferation by ATRA in RL95-2 cells, but simultaneous knockdown of RARα and RARß could block its effect on proliferation. RARα and RARß knockdown dose dependently reduced the inhibition of migration by ATRA, but the effect was more pronounced with RARß knockdown than with RARα knockdown. We confirmed that RARß gene was directly regulated by ATRA in microarray and real-time reverse transcription polymerase chain reaction. Furthermore, the RARß agonist (BMS453) significantly suppressed proliferation of RL95-2 cells. In immunohistochemical analysis, RARα expression was positively correlated with tumor grade, and RARß showed the opposite tendency in endometrial cancer. CONCLUSIONS: Retinoic acid might have multiple antitumor effects, and RARß may be a potent therapeutic target in RA treatment for endometrial cancers.

Loss of myocardial retinoic acid receptor α induces diastolic dysfunction by promoting intracellular oxidative stress and calcium mishandling in adult mice.

Retinoic acid receptor (RAR) has been implicated in pathological stimuli-induced cardiac remodeling. To determine whether the impairment of RARα signaling directly contributes to the development of heart dysfunction and the involved mechanisms, tamoxifen-induced myocardial specific RARα deletion (RARαKO) mice were utilized. Echocardiographic and cardiac catheterization studies showed significant diastolic dysfunction after 16wks of gene deletion. However, no significant differences were observed in left ventricular ejection fraction (LVEF), between RARαKO and wild type (WT) control mice. DHE staining showed increased intracellular reactive oxygen species (ROS) generation in the hearts of RARαKO mice. Significantly increased NOX2 (NADPH oxidase 2) and NOX4 levels and decreased SOD1 and SOD2 levels were observed in RARαKO mouse hearts, which were rescued by overexpression of RARα in cardiomyocytes. Decreased SERCA2a expression and phosphorylation of phospholamban (PLB), along with decreased phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase II δ (CaMKII δ) was observed in RARαKO mouse hearts. Ca2+ reuptake and cardiomyocyte relaxation were delayed by RARα deletion. Overexpression of RARα or inhibition of ROS generation or NOX activation prevented RARα deletion-induced decrease in SERCA2a expression/activation and delayed Ca2+ reuptake. Moreover, the gene and protein expression of RARα was significantly decreased in aged or metabolic stressed mouse hearts. RARα deletion accelerated the development of diastolic dysfunction in streptozotocin (STZ)-induced type 1 diabetic mice or in high fat diet fed mice. In conclusion, myocardial RARα deletion promoted diastolic dysfunction, with a relative preserved LVEF. Increased oxidative stress have an important role in the decreased expression/activation of SERCA2a and Ca2+ mishandling in RARαKO mice, which are major contributing factors in the development of diastolic dysfunction. These data suggest that impairment of cardiac RARα signaling may be a novel mechanism that is directly linked to pathological stimuli-induced diastolic dysfunction.