RT Journal Article
SR Electronic
T1 Activation of Both Protein Kinase A (PKA) Type I and PKA Type II Isozymes Is Required for Retinoid-Induced Maturation of Acute Promyelocytic Leukemia Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.081034
DO 10.1124/mol.112.081034
A1 Eric Nguyen
A1 Gro Gausdal
A1 Jacqueline Varennes
A1 Frederic Pendino
A1 Michel Lanotte
A1 Stein Doskeland
A1 Evelyne Segal-Bendirdjian
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/03/01/mol.112.081034.abstract
AB Acute promyelocytic leukemia (APL) is characterized by granulopoietic differentiation arrest at the promyelocytic stage. In most cases this defect can be overcome by treatment with all-trans-retinoic acid (ATRA) leading to complete clinical remission. Cyclic AMP signaling has a key role in retinoid treatment efficacy: it enhances ATRA-induced maturation in ATRA-sensitive APL cells (including NB4 cells) and restores it in some ATRA-resistant cells (including NB4-LR1 cells). Here, we showed that the two cell types express identical levels of the Cα catalytic subunit and comparable global cAMP-dependent protein kinase A (PKA) enzyme activity. However, the maturation-resistant NB4-LR1 cells had a PKA isozyme switch: compared to the NB4 cells, they had decreased content of the juxtanuclearly located PKA-RIIαand PKA-RIIβ and a compensatory increase of the generally cytoplasmically distributed PKA-RIα. Furthermore, PKA-RII subunit existed mainly in the less cAMP-responsive non-autophosphorylated state in the NB4-LR1 cells. We showed by using isozyme-specific cAMP analog pairs that both PKA-I and PKA-II had to be activated to achieve maturation in NB4-LR1 as well as NB4 cells. Therefore, special attention should be paid to activate not only PKA-I, but also PKA-II in attempts to enhance ATRA-induced APL maturation in a clinical setting.