Promyelocytic leukemia retinoid signaling targets regulate apoptosis,tissue factor and thrombomodulin expression.

BACKGROUND AND OBJECTIVES Retinoids are involved in cell differentiation, morphogenesis, proliferation and antineoplasic processes. Thus, the retonoic acid receptor (RARalpha) agonist, AM80, regulates tissue factor (TF), thrombomodulin (TM) expression and granulocytic differentiation in promyelocytic cells, while the RARgamma-selective retinoid, CD437, inhibits in vitro cell proliferation and induces apoptosis. The mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K) pathways constitute key integration points along the signal transduction cascades that link diverse extracellular stimuli to proliferation, differentiation and survival. DESIGN AND METHODS PI3K and MEK/ERK kinase-dependent pathways were examined as potential targets of retinoid signaling. Likewise, by using specific inhibitors, the role of those kinases in retinoid-induced granulocytic differentiation, apoptosis, and TF and TM expression n NB4 cells were analyzed. RESULTS AM80-treated NB4 cells had increased PI3K activity and phosphoinositide turnover. High steady-state pERK-1/-2 activity levels were not significantly changed by AM80. Yet, PI3K inhibitor LY294002 significantly reduced AM80-elicted ERK-1/-2 activity. Thus, the PI3K pathway might contribute to elevated ERK-1/-2 activity in NB4 cells. Inhibition of the PI3K and MEK/ERK pathways reversed AM80-induced granulocytic differentiation, TF down-regulation and TM induction. Besides, CD437 significantly reduced ERK-1/-2 activity of NB4 cells. Further ERK-1/-2 activity inhibition with the MEK inhibitor, PD98059, increased the retinoid pro-apoptotic effect with an additive effect. INTERPRETATION AND CONCLUSIONS Regardless the different regulation of PI3K and MAPK pathways promoted by AM80 and CD437, there is a varying degree of cross-talk between these pathways in the control of the overall response of promyelocytic cells to retinoids. Thus, disruption of targeted pathways, together with specific retinoids, might be an effective therapeutic treatment for acute promyelocytic leukemia.