c-Jun N-terminal kinase 2 (JNK2) antagonizes the signaling of differentiation by JNK1 in human myeloid leukemia cells resistant to vitamin D

• Published in: Leukemia research Vol. 33; no. 10; pp. 1372 - 1378
• Main Authors: Chen-Deutsch, Xiangwen, Garay, Edward, Zhang, Jing, Harrison, Jonathan S, Studzinski, George P
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2009
• Subjects: AML; Antioxidants - pharmacology; Cell Differentiation - drug effects; Cell Division - drug effects; Differentiation; Diterpenes, Abietane - pharmacology; Drug resistance; Drug Resistance, Neoplasm; Enzyme Inhibitors - pharmacology; Hematology, Oncology and Palliative Medicine; HL-60 Cells - drug effects; Humans; Imidazoles - pharmacology; JNK pathway; Leukemia, Myeloid, Acute - blood; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Mitogen-Activated Protein Kinase 9 - deficiency; Mitogen-Activated Protein Kinase 9 - genetics; Mitogen-Activated Protein Kinase 9 - metabolism; Nuclear localization; Plant Extracts - pharmacology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - blood; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proto-Oncogene Proteins c-jun - genetics; Pyridines - pharmacology; RNA, Small Interfering - genetics; Transcription Factor AP-1 - genetics; Tretinoin - therapeutic use; Vitamin D; AML; JNK pathway; Nuclear localization; Vitamin D; Differentiation; Drug resistance
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2009.03.003

Abstract 1,25-Dihydroxyvitamin D3 (1,25D) induces differentiation of myeloid leukemia cells, but resistant cells are also encountered. We studied the mechanistic basis for the resistance in a model system using enhancers of 1,25D, the antioxidant carnosic acid and a kinase inhibitor SB202190. Knock-down (KD) of JNK2p54 unexpectedly increased the intensity of differentiation induced by the 1,25D, carnosic acid and SB202190 (DCS) combination. This was associated with upregulation of activated JNK1p46, and the transcription factors regulated by the JNK pathway, c-Jun, ATF2 and JunB, as well as C/EBP β. In contrast, KD of JNK1p46 reduced the intensity of DCS-induced differentiation, and partially abrogated activation of c-Jun/AP-1 transcription factors.