The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts

Harrison, Jonathan S.; Wang, Xuening; Studzinski, George P.

doi:10.18632/oncotarget.8998

Cited by 17 publications

(12 citation statements)

References 54 publications

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“…Accordingly, we confirmed that the depletion of VDR by partial knock down (KD) by either CRISPR/Cas9 or siRNA reduces ECD in HL60 cells ( Fig. 2A, and previous publications [2,16]) and in U937 cells (Suppl. Figs S2A, B).…”

Section: Knock Down Of Vdr By Crispr/cas9 or Sirna In Aml Cell Lines supporting

confidence: 89%

Participation of vitamin D-upregulated protein 1 (TXNIP)-ASK1-JNK1 signalosome in the enhancement of AML cell death by a post-cytotoxic differentiation regimen

Wang

Nachliely

Harrison

et al. 2019

The Journal of Steroid Biochemistry and Molecular Biology

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Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in vitro model of a potential therapeutic regimen for AML, the activity of cytarabine (AraC) is enhanced by a sequential treatment with a combination of the vitamin D2 analog Doxercalciferol (D2) and the plant-derived antioxidant carnosic acid (CA) Importantly, the enhancement occurred selectively in patient-derived AML blasts, but not in the normal bone marrow cells. We now demonstrate that TXNIP, previously known as Vitamin D up-regulated protein 1 (VDUP1) [PMID 808674] plays a part in signaling cell death (CD) in this regimen. This is shown by the reduced CD when TXNIP protein levels are decreased by the CRISPR/CAS9 or RNAi technology. Further, we show that direct activation of ASK1 kinase by TXNIP is required for the optimal transmission of the CD signal to apoptotic machinery, regulated by JNK and BIM. These studies provide a rationale for a projected clinical trial of this vitamin D-based new therapeutic regimen for AML.

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Section: Knock Down Of Vdr By Crispr/cas9 or Sirna In Aml Cell Lines supporting

confidence: 89%

Participation of vitamin D-upregulated protein 1 (TXNIP)-ASK1-JNK1 signalosome in the enhancement of AML cell death by a post-cytotoxic differentiation regimen

Wang

Nachliely

Harrison

et al. 2019

The Journal of Steroid Biochemistry and Molecular Biology

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“…These compounds, an analog of vitamin D2 Doxercalciferol (D2) and a plant-derived antioxidant carnosic acid (CA), have a powerful differentiating effect when combined, and this increases the cytotoxicity of AraC to AML blasts. Importantly, this action is selective for neoplastic cells, as the enhancement of cell death by this differentiation agent combination has no observable effect on the normal bone marrow cells (13, 14).…”

Section: Introductionmentioning

confidence: 99%

“…The initial investigation of the mechanism responsible for the enhancement of AraC-induced cell death by treating cells that have damaged DNA with a differentiation agent combination (D2/CA) has revealed a paradoxical tumor suppressor-like activity of BRAF. We found that reducing the level or inhibiting the kinase activity of BRAF diminishes the ability of D2/CA to enhance ALM cell death (13). Also, D2/CA increases BRAF expression in a VDR-dependent manner, which correlates with the increased levels of the DNA damage marker H2AX (14).…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Beute

Harrison

et al. 2018

The Journal of Steroid Biochemistry and Molecular Biology

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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.

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“…To understand the basis of this resistance, we must first understand the ATRA-induced differentiation program. Toward this challenge, lessons learned in model systems, such as the lineage-uncommitted human myeloblastic cell line HL-60 reported to closely resemble patient derived cells 10 , could inform our analysis of the differentiation programs occurring in patients. Patient derived HL-60 leukemia cells have been a durable experimental model since the 1970’s to study differentiation 11 .…”

Section: Introductionmentioning

confidence: 99%

An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program

Tasseff

Jensen

Congleton

et al. 2017

Sci Rep

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In this study, we present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes reinforcing feedback between an ATRA-inducible signalsome complex involving many proteins including Vav1, a guanine nucleotide exchange factor, and the activation of the mitogen activated protein kinase (MAPK) cascade. We decomposed the effective model into three modules; a signal initiation module that sensed and transformed an ATRA signal into program activation signals; a signal integration module that controlled the expression of upstream transcription factors; and a phenotype module which encoded the expression of functional differentiation markers from the ATRA-inducible transcription factors. We identified an ensemble of effective model parameters using measurements taken from ATRA-induced HL-60 cells. Using these parameters, model analysis predicted that MAPK activation was bistable as a function of ATRA exposure. Conformational experiments supported ATRA-induced bistability. Additionally, the model captured intermediate and phenotypic gene expression data. Knockout analysis suggested Gfi-1 and PPARg were critical to the ATRAinduced differentiation program. These findings, combined with other literature evidence, suggested that reinforcing feedback is central to hyperactive signaling in a diversity of cell fate programs.

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The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts

Cited by 17 publications

References 54 publications

Participation of vitamin D-upregulated protein 1 (TXNIP)-ASK1-JNK1 signalosome in the enhancement of AML cell death by a post-cytotoxic differentiation regimen

Participation of vitamin D-upregulated protein 1 (TXNIP)-ASK1-JNK1 signalosome in the enhancement of AML cell death by a post-cytotoxic differentiation regimen

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

An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program

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