The retinoic acid receptor/CaMKII interaction: pharmacologic inhibition of CaMKII enhances the differentiation of myeloid leukemia cells.
Certain myeloid leukemia cells, particularly the acute promyelocytic leukemia (APL) subset, undergo terminal granulocytic differentiation in response to retinoic acid (RA). RA mediates its biologic effects through specific retinoic acid receptors (RARs) which serve as ligand-activated nuclear transcription factors. The Ca(++)/calmodulin-dependent protein kinases (CaMKs) are multifunctional serine/threonine kinases that are regulated by Ca(++) signaling. We have observed significant cross-talk between these Ca(++) and RA signaling pathways that regulates the differentiation of myeloid leukemia cells. We observe that CaMKIIgamma is the CaMK that is predominantly expressed in myeloid cells. This enzyme localizes to the promoter of RAR target genes, physically interacts with and phosphorylates RARalpha and inhibits RAR transcriptional activity. KN-62, a pharmacological inhibitor of the CaMKs, enhances both retinoic acid receptor transcriptional activity as well as the terminal in vitro differentiation of certain myeloid leukemia cell lines including HL-60. However, this compound, as well as related synthetic analogs that enhance HL-60 terminal differentiation, fails to inhibit the growth of HL-60 xenografts in NOD-SCID mice likely because of the unfavorable pharmacokinetics displayed by these compounds. Nevertheless, our observations suggest that CaMKIIgamma may provide a new therapeutic target for the treatment of the RA-responsive human myeloid leukemias.
Si
Jutong
J
Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, Seattle, WA 98109, USA.
Mueller
LeMoyne
L
Schuler
Aaron
A
Simon
Julian
J
Collins
Steven J
SJ
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D002454:Cell Differentiation; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000378:metabolism
D004791:Enzyme Inhibitors; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2