p38αMAPK interacts with and inhibits RARα: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells

Abstract

All-trans retinoic acid (ATRA) is the only clinically useful differentiating agent, being used 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. Here, we provide evidence that pharmacological inhibition of the mitogen-activated protein kinase, p38a, 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. P38a inhibits ligand-dependent transactivation of the nuclear retinoic acid receptor, RARa, and the derived chimeric protein expressed in the majority of APL cases, PML-RARa. Inhibition is the consequence of ligand-independent binding of p38a, which results in stabilization of RARa and PML-RARa via blockade of their constitutive degradation by the proteasome. The inhibitory effect requires a catalytically active p38a and direct physical interaction with RARa and PML-RARa. Ser-369 in the E-region of RARa is essential for the binding of p38a and the ensuing functional effects on the activity of the receptor.

E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα

“…14,41 Interestingly, we found that E2F1 directly interacts with RARα and promotes ubiquitination-proteasome-mediated degradation of RARα (Fig. 5 and 6).…”

Bortezomib Sensitizes Human Acute Myeloid Leukemia Cells to All-Trans-Retinoic Acid–Induced Differentiation by Modifying the RARα/STAT1 Axis

“…Moreover, Gianni and group also reported that Pin1 or p38a pharmacologic inhibition stabilized RARa and PML-RARa by blocking their constitutive proteasomal degradation and sensitized myeloid leukemia cells to retinoids (46,47). To this end, there is much evidence indicating that controlling RARa stability or activation may be an effective strategy to improve retinoid efficacy in AML.…”

Inhibition of p38 MAPK Phosphorylation Is Critical for Bestatin to Enhance ATRA-Induced Cell Differentiation in Acute Promyelocytic Leukemia NB4 Cells

“…16 Pharmacological inhibition or silencing of p38 MAPK sensitizes APL cell lines to the antiproliferative and cytodifferentiating activity of ATRA. 17 Studies are underway to extend our findings to primary leukemic cells for overcoming the limitations of this study.…”

“…17 Inhibition of p38a MAPK resulted in stabilization of RARa and the derived chimeric protein expressed in the majority of APL cases, PML-RARa, via blockade of their constitutive degradation by the proteasome, and promoted liganddependent transactivation of the nuclear RARa and PML-RARa. 17 We speculated that Bestatin potentiated the effect of ATRA possibly via the similar mechanisms.…”