JNK1 as a signaling node in VDR-BRAF induction of cell death in AML

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 177; pp. 149 - 154
• Main Authors: Wang, Xuening, Beute, William K, Harrison, Jonathan S, Studzinski, George P
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2018
• Subjects: Acute myeloid leukemia; Antimetabolites, Antineoplastic - pharmacology; Braf; Carnosic acid; Cell Death; Cytarabine - pharmacology; Foxo; HL-60 Cells; Humans; Jnk; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Mitogen-Activated Protein Kinase 8 - genetics; Mitogen-Activated Protein Kinase 8 - metabolism; Mitogen-Activated Protein Kinase 9 - genetics; Mitogen-Activated Protein Kinase 9 - metabolism; Proto-Oncogene Proteins B-raf - genetics; Receptors, Calcitriol - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; Signal Transduction; Vitamin D; H2AX; Foxo; JNK; DOT1L; Carnosic acid; CRAF; AraC; FOXO3; AP-1; HOXA9; Vitamin D; IDH1/2; VDD; CA; Crk-L; p38MAPK; AML; MLL1; JUN; NPM1; VDR; ASK1; BNIP3; FAB; BIM; AKT; BRAF; D2; BCL2; Acute myeloid leukemia; Braf; Jnk
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2017.07.005

Potential signals downstream from VDR-BRAF pathway in the context of DNA damage. In this cell context, solid lines show proven signaling; bolded if shown here, and interrupted lines show signaling that needs further study. [Display omitted] •In AML cells with DNA damage attempted differentiation results in apoptosis instead.•Enhanced cell death is facilitated by an enhanced expression of VDR and BRAF.•The execution of cell death in this setting may be signaled by JNK activation. Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant diseases. However, given the strong preclinical evidence of anti-neoplastic activity and the epidemiological associations suggesting that vitamin D compounds may have a place in cancer therapy, attempts are continuing to devise new approaches to their therapeutic use. This laboratory has developed a strategy to enhance the effectiveness of the currently standard therapy of Acute Myeloid Leukemia (AML) by the immediate addition of the vitamin D2 analog Doxercalciferol combined with the plant polyphenol-derived Carnosic acid to AML cells previously treated with Cytarabine (AraC). Enhancement of AML cell death was noted to be dependent on VDR and BRAF kinase. Here we document that the stress-related kinase JNK is an important additional component of cell death enhancement in this protocol. Either the Knock-down or the inhibition of JNK activity reduced the enhancement of AraC-induced cell death, and we show that JNK signaling to the apoptosis regulator BIM and Caspase executioners of cell death are downstream of VDR and BRAF. A clear understanding of the molecular basis for the increased efficacy of AraC in the therapy of AML is expected to bring this regimen to a clinical trial.