Abstract 1836: p38α MAPK interacts with and inhibits RARα: Suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells

Abstract

Abstract All-trans retinoic acid (ATRA) is the only clinically useful differentiating agent, being employed in the treatment of acute promyelocytic leukemia (APL). The use of ATRA in other types of acute myelogenous leukemia (AML) calls for the identification of novel strategies aimed at increasing its therapeutic activity. One possible strategy to improve the efficacy of retinoids is to identify non-retinoid compounds that enhance the activity of ATRA, focusing on the mechanisms controlling the stability/activation of the nuclear retinoid receptors expressed in the AML blast. An important mechanism modulating the activity of the RAR-containing transcriptional complexes is phosphorylation of RARs and accessory proteins, such as co-repressors and co-activators. The mitogen activated kinase p38alpha, cyclin-dependent kinase 7 (CDK7) and mitogen-and stress-activated kinase (MSK1) stand out as critical determinants in the process. p38alpha is often increased and/or activated in AML blasts and it represents an important pharmacological target as well as a potential determinant of ATRA sensitivity in these cells. Here, we provide evidence that pharmacological inhibition of the mitogen-activated- protein-kinase, p38alpha, or silencing of the corresponding gene sensitizes APL and AML cell lines, as well as primary cultures of AML blasts to the anti-proliferative and cyto-differentiating activity of ATRA and synthetic retinoids. P38alpha inhibits ligand-dependent transactivation of the nuclear retinoic acid receptor, RARalpha, and the derived chimeric protein expressed in the majority of APL cases, PML-RARalpha. Inhibition is the consequence of ligand-independent binding of p38alpha which results in stabilization of RARalpha and PML-RARalpha via blockade of their constitutive degradation by the proteasome. Our data indicate that p38alpha inhibition causes a preferential increase in the relative amounts of RARalpha over those of PML-RARalpha. The inhibitory effect requires a catalytically active p38alpha and direct physical interaction with RARalpha and PML-RARalpha. Ser-369 in the E-region of RARalpha is essential for the binding of p38alpha and the ensuing functional effects on the activity of the receptor. In conclusion, our results add a further layer of complexity to the mechanisms controlling retinoid receptors’ activity and provide the rationale for the use of novel strategies in the treatment of AML patients with a cyto-differentiating approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1836. doi:1538-7445.AM2012-1836