TY - JOUR
T1 - The rationale for deltanoids in therapy for myeloid leukemia
T2 - Role of KSR-MAPK-C/EBP pathway
AU - Studzinski, George P.
AU - Wang, Xuening
AU - Ji, Yan
AU - Wang, Qing
AU - Zhang, Yingyu
AU - Kutner, Andrzej
AU - Harrison, Jonathan S.
N1 - Funding Information:
We thank Dr. Milan Uskokovic, BioXell, Nutley, NJ, for the gift of 1α,25-dihydroxyvitamin D 3 and Dr. Steinmeyer, Schering AG, Berlin, Germany, for the 1α,25-dihydroxyvitamin D 3 antagonist ZK 159222. We also thank Dr. Michael Danilenko, Ben-Gurion University of the Negev, Israel, Dr. Ewa Marcinkowska, University of Wroclaw, Poland and Edward Garay, UMDNJ, for comments on the manuscript. This study was supported by NIH Grant RO1-CA 44722 from the National Cancer Institute.
PY - 2005/10
Y1 - 2005/10
N2 - The evidence for the promising potential for derivatives of Vitamin D (deltanoids) in the treatment of myeloid leukemias is increasing, but currently is not matched by the understanding of the precise mechanisms by which these anti-neoplastic effects are achieved. Unlike solid tumors in which growth retardation by deltanoids appears to result from inhibition of cell proliferation and the promotion of cell death by apoptosis, control of myeloid leukemia proliferation by deltanoids results from the induction of differentiation of the immature myelo-monocytic cells towards functional monocytic cells. We present here the accumulating evidence that a pathway that is initiated by deltanoid activation of Vitamin D receptor (VDR) and leads to monocytic differentiation of human myeloblastic HL60 cells, includes the MEK-ERK and JNK mitogen-activated protein kinases (MAPKs), their positive and negative regulators and a downstream effector C/EBPβ. As in other cells, the abundance of VDR protein increases shortly after an exposure of HL60 cells to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D 3). Other early events include a parallel upregulation of kinase suppressor of Ras (KSR-1) and the activation of the ERK MAPK pathway and data suggest that KSR-1 acts to amplify the signal provided by low concentrations of 1α,25(OH)2 D3. Maintenance of monocytic differentiation may be enhanced by JNK, but diminished by p38, MAPK signaling. Downstream, one of the targets of these pathways is C/EBPβ, which can directly interact with the promoter for CD14, a gene characteristically expressed in monocytes. Importantly, in freshly obtained acute myeloid leukemia (AML)-M2 cells exposed to PRI-2191, a novel deltanoid with a modified side chain, upregulation of C/EBPβ paralleled the induction of monocytic differentiation. These data provide a basis for the hypothesis that deltanoid-induced upregulation of C/EBPβ bypasses the block to granulocytic differentiation in myeloid leukemia cells by redirecting the cells to monocytic differentiation.
AB - The evidence for the promising potential for derivatives of Vitamin D (deltanoids) in the treatment of myeloid leukemias is increasing, but currently is not matched by the understanding of the precise mechanisms by which these anti-neoplastic effects are achieved. Unlike solid tumors in which growth retardation by deltanoids appears to result from inhibition of cell proliferation and the promotion of cell death by apoptosis, control of myeloid leukemia proliferation by deltanoids results from the induction of differentiation of the immature myelo-monocytic cells towards functional monocytic cells. We present here the accumulating evidence that a pathway that is initiated by deltanoid activation of Vitamin D receptor (VDR) and leads to monocytic differentiation of human myeloblastic HL60 cells, includes the MEK-ERK and JNK mitogen-activated protein kinases (MAPKs), their positive and negative regulators and a downstream effector C/EBPβ. As in other cells, the abundance of VDR protein increases shortly after an exposure of HL60 cells to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D 3). Other early events include a parallel upregulation of kinase suppressor of Ras (KSR-1) and the activation of the ERK MAPK pathway and data suggest that KSR-1 acts to amplify the signal provided by low concentrations of 1α,25(OH)2 D3. Maintenance of monocytic differentiation may be enhanced by JNK, but diminished by p38, MAPK signaling. Downstream, one of the targets of these pathways is C/EBPβ, which can directly interact with the promoter for CD14, a gene characteristically expressed in monocytes. Importantly, in freshly obtained acute myeloid leukemia (AML)-M2 cells exposed to PRI-2191, a novel deltanoid with a modified side chain, upregulation of C/EBPβ paralleled the induction of monocytic differentiation. These data provide a basis for the hypothesis that deltanoid-induced upregulation of C/EBPβ bypasses the block to granulocytic differentiation in myeloid leukemia cells by redirecting the cells to monocytic differentiation.
KW - C/EBP
KW - Differentiation
KW - KSR-1
KW - MAPKs
KW - Myeloid leukemia
KW - Vitamin D
UR - http://www.scopus.com/inward/record.url?scp=27544483645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27544483645&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2005.06.010
DO - 10.1016/j.jsbmb.2005.06.010
M3 - Article
C2 - 16046262
AN - SCOPUS:27544483645
VL - 97
SP - 47
EP - 55
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
SN - 0960-0760
IS - 1-2
ER -