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Redox Control of Retinoic Acid Receptor Activity: A Novel Mechanism for Retinoic Acid Resistance in Melanoma Cells¹

Departments of Otolaryngology (K.D., L.W., R.A.S.) and Medicine (J.S.L., D.V.F.), Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Remco A. Spanjaard, Ph.D., Boston University School of Medicine, Cancer Research Center, 715 Albany Street R903, Boston, Massachusetts 02118. E-mail: rspan{at}bu.edu

Retinoic acid (RA) slows growth and induces differentiation of tumor cells through activation of RA receptors (RARs). However, melanoma cell lines display highly variable responsiveness to RA, which is a poorly understood phenomenon. By using Northern and Western blot analyses, we show that RA-resistant A375 and RA-responsive S91 melanoma cells express comparable levels of major components of RAR-signaling pathways. However, A375 cells have substantially higher intracellular reactive oxygen species (ROS) levels than S91 cells. Lowering ROS levels in A375 cells through hypoxic culture conditions restores RAR-dependent trans-activity, which could be further enhanced by addition of the antioxidant N-acetyl-cysteine. Hypoxia also enhances RAR activity in the moderately RA-responsive C32 cells, which have intermediate ROS levels. Conversely, increasing oxidative stress in highly RA-responsive S91 and B16 cells, which have low ROS levels, by treatment with H₂O₂ impairs RAR activity. Consistent with these observations, RA more potently inhibited the proliferation of hypoxic A375 cells than that of normoxic cells. Oxidative states diminish, whereas reducing conditions enhance, DNA binding of retinoid X receptor/RAR heterodimers in vitro, providing a molecular basis for the observed inverse correlation between RAR activity and ROS levels. The redox state of melanoma cells provides a novel, epigenetic control mechanism of RAR activity and RA resistance.